Compounds acting at multiple prostaglandin receptors giving a general anti-inflammatory response

ABSTRACT

The present invention provides a compound, that is a 1-({halo-2-[(2-hydrocarbyl or substituted hydrocarbyl)oxy]phenyl}methyl)-(fused bicyclic nitrogen heteroaryl) carboxylic acid or an ester or sulfonamide thereof. The compound may be represented by the following formula 
     
       
         
         
             
             
         
       
     
     Wherein R 1 , R 2 , R 3 , R 4  A, X, W, Z and Y are as defined in the specification. The compounds may be administered to treat DP, FP, EP1, TP and/or EP4 receptor-mediated diseases or conditions.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 61/578,640, filed Dec. 21, 2011, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compounds, to processes for their preparation,to pharmaceutical compositions containing them and to their use inmedicine, in particular their use in the treatment of conditionsmediated by the action of ligands for the DP₁, FP, TP, EP₁ and EP₄prostaglandin (PG) receptors. The present compounds have the generalstructure shown below and act at different prostaglandin receptors tothereby provide a general anti-inflammatory response.

2. Summary of the Related Art

The EP₁ receptor is a 7-transmembrane receptor and its natural ligand isthe prostaglandin PGE₂. PGE₂ also has affinity for the other EPreceptors (types EP₂, EP₃ and EP₄). The EP₁ receptor is associated withsmooth muscle contraction, pain (in particular inflammatory, neuropathicand visceral), inflammation, allergic activities, renal regulation andgastric or enteric mucus secretion.

Prostaglandin E₂ (PGE₂) exerts allodynia through the EP₁ receptorsubtype and hyperalgesia through EP₂ and EP₃ receptors in the mousespinal cord. Furthermore, it has been shown that in the EP₁ knock-outmouse pain-sensitivity responses are reduced by approximately 50%. EP₁receptor antagonist (ONO-8711) reduces hyperalgesia and allodynia in arat model of chronic constriction injury and inhibits mechanicalhyperalgesia in a rodent model of post-operative pain. The efficacy ofEP₁ receptor antagonists in the treatment of visceral pain in a humanmodel of hypersensitivity has been demonstrated. Thus, selectiveprostaglandin ligands, agonists or antagonists, depending on whichprostaglandin E receptor subtype is being considered, haveanti-inflammatory, antipyretic and analgesic properties similar to aconventional non-steroidal anti-inflammatory drug, and in addition,inhibit hormone-induced uterine contractions and have anti-cancereffects. These compounds have a diminished ability to induce some of themechanism-based side effects of NSAIDs which are indiscriminatecyclooxygenase inhibitors. In particular, the compounds have a reducedpotential for gastrointestinal toxicity, a reduced potential for renalside effects, a reduced effect on bleeding times and a lessened abilityto induce asthma attacks in aspirin-sensitive asthmatic subjects.Moreover, as a result of sparing potentially beneficial prostaglandinpathways, these agents may have enhanced efficacy and safety over NSAIDSand/or COX-2 inhibitors. EP₄ receptors have also been implicated inpain, hyperalgesia, allodynia, and inflammation. (See Pub. No. US2005/0065200 which is hereby incorporated by reference for otherdiseases that may be treated by EP4 receptor antagonists.)

The TP (also known as TxA₂) receptor is a prostanoid receptor subtypestimulated by the endogenous mediator thromboxane. Activation of thisreceptor results in various physiological actions primarily incurred byits platelet aggregatory and smooth muscle constricting effects, thusopposing those of prostacyclin receptor activation.

TP receptors have been identified in human kidneys in the glomerulus andextraglomerular vascular tissue. Activation of TP receptors constrictsglomerular capillaries and suppresses glomerular filtration ratesindicating that TP receptor antagonists could be useful for renaldysfunction in glomerulonephritis, diabetes mellitus and sepsis.

Activation of TP receptors induces bronchoconstriction, an increase inmicrovascular permeability, formation of mucosal edema and mucussecretion, which are typical characteristic features of bronchialasthma. TP antagonists have been investigated as potential asthmatreatments resulting in, for example, orally active Seratrodast(AA-2414). Ramatroban is another TP receptor antagonist currentlyundergoing phase III clinical trials as an anti-asthmatic compound.

Since DP₁ receptor stimulation may trigger an asthmatic response incertain individuals, compounds that have DP₁ antagonist properties maybe useful as anti-asthmatic drugs. (See Pub. No. 2004/0162323 which ishereby incorporated by reference in its entirety for the disclosure ofother diseases and conditions that may be treated with DP antagonists.)

Finally, the FP receptor modulates intraocular pressure and mediatessmooth muscle contraction of the sphincter muscles in thegastrointestinal tract and the uterus. Thus, antagonists of the FPreceptor are useful for treating reproductive disorders. (See U.S. Pat.No. 6,511,999 which is hereby incorporated by reference in its entiretyfor other diseases and conditions that may be treated with FP receptorantagonists.)

As further background for the present invention, see US Published PatentApplication 2007/0060596 which is hereby incorporated by reference inits entirety.

BRIEF SUMMARY OF THE INVENTION

This invention provides compounds, that are 1-({halo-2-[(2-hydrocarbylor substituted hydrocarbyl)oxy]phenyl}methyl)-(fused bicyclic nitrogenheteroaryl)carboxylic acids, or esters and sulfonamides thereof, such as1-({halo-2-[(2-hydrocarbyl or substitutedhydrocarbyl)oxy]phenyl}methyl)-(2,3 benzopyrrole or 2,3benzo-1,2-diazole)carboxylic acids, or esters and sulfonamides thereofe.g. 1-({5-halo-2-[(2-alkyl)oxy]phenyl}methyl)-(2,3 benzopyrrole or 2,3benzo-1,2-diazole)-5-carboxylic acids or esters or sulfonamides thereof.Said fused bicyclic nitrogen heteroaryl may be indole, isoindole,indolizine, benzotriazole, or purine. Preferably the ester orsulfonamide is an alkyl ester or sulfonamide. Preferably said halo ischloro or bromo and said alkyl is a branched chain alkyl having from 4to 7 carbons, e.g. 3-ethylbutyl or 2-methylpropyl.

The invention further relates to pharmaceutical compositions containingthe above compounds in combination with a pharmaceutically-acceptableexcipient and to their use in medicine, in particular their use in thetreatment of conditions mediated by the action of ligands for the DP₁,FP, EP₁ and EP₄ prostaglandin (PG) receptors. The compounds of thisinvention are also useful for treating conditions mediated by the actionof ligands for the thromboxane (TP) receptor.

Some embodiments of the present invention include:1. A compound, that is a 1-({halo-2-[(2-hydrocarbyl or substitutedhydrocarbyl)oxy]phenyl}methyl)-(fused bicyclic nitrogenheteroaryl)carboxylic acid, or ester or sulfonamide thereof, and saidhydrocarbyl may be a branched chain alkyl having from 4 to 7 carbons,e.g. 3-ethylbutyl or 2-methylpropyl.2. A compound according to paragraph 1 wherein said compound is a1-({5-halo-2-[(2-alkyl)oxy]phenyl}methyl)-(2,3 benzopyrrole or 2,3benzo-1,2-diazole)-5-carboxylic acid or ester or sulfonamide thereof.3. A compound according to paragraph 2 wherein said ester or sulfonamideis an alkyl ester or sulfonamide.4. A compound according to paragraph 3, wherein said halo is selectedfrom the group consisting of chloro and bromo.5. A compound according to paragraph 3 wherein said alkyl is a branchedchain alkyl having from 4 to 7 carbons.6. A compound according to paragraph 3 wherein said alkyl is selectedfrom the group consisting of 2-ethylbutyl and 2-methylpropyl.7. A compound represented by the following formula

wherein X is N or CR₇;A is N or CR₇ with the proviso that at least one A is N and when each Ais N, R₂ is absent;Y is (CH₂)_(m) wherein m is 0 or an integer of from 1 to 3;Z is selected from the group consisting of O, S, SO, SO₂ and (CH₂)_(p),wherein p is 0 or an integer of from 1 to 3;W is hydrocarbyl or substituted hydrocarbyl;R₁ is selected from the group consisting of OR₇, NH₂, N(R₇)₂, andN(R₇)SO₂R₇;R₂ is selected from the group consisting of H, hydroxyl, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxyl halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;R₃ is selected from the group consisting of H, hydroxyl, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;R₄ is selected from the group consisting of H, hydroxyl, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy; and,R₇ is selected from the group consisting of H, hydrocarbyl andsubstituted hydrocarbyl.8. The compound of paragraph 7 wherein R₇ is selected from the groupconsisting of carbocyclic aryl and alkyl.9. The compound of paragraph 7 wherein said compound is represented bythe formula II:

10. The compound of paragraph 9 wherein R₁ is OH.11. The compound of paragraph 9 wherein R₂ is selected from the groupconsisting of H, alkyl and halogen substituted alkyl.12. The compound of paragraph 11 wherein R₂ is selected from the groupconsisting of fluoro-substituted alkyl.13. The compound of paragraph 10 wherein X is N or CH.14. The compound of paragraph 7 wherein said compound is represented byformula III.

15. The compound of paragraph 10 wherein R₃ is selected from the groupconsisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro,amino, cyano and hydroxy, halogen, nitro, amino and cyano-substitutedalkyl, aryl, alkoxy or aryloxy.16. The compound of paragraph 10 wherein R₃ is chloro or bromo.17. The compound of paragraph 10 wherein R₄ is selected from the groupconsisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro,amino, cyano and hydroxy, halogen, nitro, amino and cyano-substitutedalkyl, aryl, alkoxy or aryloxy.18. The compound of paragraph 10 wherein R₄ is H.19. The compound of paragraph 10 wherein Y is absent, i.e. n is 0.20. The compound of paragraph 10 wherein Z is 0.21. The compound of paragraph 10 wherein W is selected from the groupconsisting of alkyl, aryl, alkoxy, aryloxy and hydroxy, halogen, nitro,amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy.22. The compound of paragraph 10 wherein W is alkyl.23. The compound of paragraph 10 wherein W is a branched chain alkyl.24. The compound of paragraph 10 wherein W is 2-ethylbutyl or2-methylpropyl.25. The compound of paragraph 10 that is selected from the groupconsisting of:

-   1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indole-5-carboxylic acid,-   1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic    acid,-   1-(2-Chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid,-   1-(2-Bromo-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid,-   1-[2-Bromo-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic acid,-   1-[2-Chloro-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylic    acid,-   1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid,-   1-(2-Benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic acid,-   1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic    acid,-   1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid,-   1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid,-   1-(2-Benzyloxy-5-bromo-benzyl)-1H-indazole-5-carboxylic acid,-   1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic    acid,-   1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid,-   1-(5-Bromo-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid,-   2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid and-   2-(5-Bromo-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid.-   1-(2-(Trifluoromethyl)-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic    acid,-   1-(5-Bromo-2-cyclopropyl-2-methylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid,-   1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylic    acid,-   1-(5-Bromo-2-isobutoxy-benzyl)-3-methyl-1H-indazole-5-carboxylic    acid,-   1-(5-Bromo-2-isobutoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic    acid, and,-   1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic    acid.    26. A method comprising administering a compound having the    following formula

X is N or CR₇;

A is N or CR₇ with the proviso that at least one A is N and when each Ais N, R₂ is absent;Y is (CH₂)_(m) wherein m is 0 or an integer of from 1 to 3;Z is selected from the group consisting of O, S, SO, SO₂ and (CH₂)_(p),wherein p is 0 or an integer of from 1 to 3;W is hydrocarbyl or substituted hydrocarbyl;R₁ is selected from the group consisting of OR₇, N(R₇)₂, and N(R₇)SO₂R₇;R₂ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;R₃ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;R₄ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy; and,R₇ is selected from the group consisting of H, hydrocarbyl andsubstituted hydrocarbyl, e.g. carbocyclic aryl and alkyl.27. The method of paragraph 26 wherein said compound is administered totreat DP1, FP, EP1, TP and/or EP4 receptor mediated diseases orconditions.28. The method of paragraph 27 wherein said condition or disease isrelated to inflammation.29. The method of paragraph 27 wherein said DP1, FP, EP1, TP and/or EP4receptor mediated condition or disease is selected from the groupconsisting of allergic conditions, asthma, allergic asthma, allergicrhinitis, uveitis and related disorders, atherosclerosis, bloodcoagulation disorders, bone disorders, cancer, cellular neoplastictransformations, chronic obstructive pulmonary diseases and other formsof lung inflammation, congestive heart failure, diabetic retinopathy,diseases or conditions requiring a treatment of anti-coagulation,diseases requiring control of bone formation and resorption,endometriosis, fertility disorders, gangrene, glaucoma, hyperpyrexia,immune and autoimmune diseases, inflammatory conditions, metastic tumorgrowth, migraine, mucus secretion disorders, nasal congestion, nasalinflammation, occlusive vascular diseases, ocular hypertension, ocularhypotension, osteoporosis, pre-term labor rheumatoid arthritis, pain,perennial rhinitis, pulmonary congestion, pulmonary hypotension,Raynaud's disease, rejection in organ transplant and by-pass surgery,respiratory conditions, hirsutism, rhinorrhea, shock, sleep disorders,and sleep-wake cycle disorders.30. The method of paragraph 27 wherein said compound is administered asa surgical adjunct in ophthalmology for cataract removal and artificiallens insertion, ocular implant procedures, photorefractive radialkeratotomy and other ophthamological laser procedures.31. The method of paragraph 27 wherein said compound is administered asa surgical adjunct in a procedure involving skin incisions, relief ofpain and inflammation and scar formation/keloids post-surgery, fortreating sports injuries and general aches and pains in muscles andjoints.32. The method of paragraph 27 wherein said DP₁, FP, EP₁, TP, and/or EP₄receptor mediated condition or disease is an EP₁ and/or EP₄ receptormediated condition or disease.33. The method of paragraph 27 wherein said DP₁, FP, EP₁, TP and/or EP₄receptor mediated condition or disease is an allergic condition.34. The method of paragraph 33 wherein said condition is dermatologicalallergy.35. The method of paragraph 27 wherein said condition is an ocularallergy.36. The method of paragraph 27 wherein said condition is a respiratoryallergy.37. The method of paragraph 27 wherein said condition or disease isselected from the group consisting of nasal congestion, rhinitis, andasthma.38. The method of paragraph 27 wherein said condition or disease isrelated to pain.39. The method of paragraph 27 wherein said condition or disease isselected from the group consisting of arthritis, migraine, and headache.40. The method of paragraph 27 wherein said condition or disease isassociated with the gastrointestinal tract.41. The method of paragraph 27 wherein said condition or disease isselected from the group consisting of peptic ulcer, heartburn, refluxesophagitis, erosive esophagitis, non-ulcer dyspepsia, infection byHelicobacter pylori, alrynitis, and irritable bowel syndrome.42. The method of paragraph 27 wherein said condition or disease isselected from the group consisting of hyperalgesia and allodynia.43. The method of paragraph 27 wherein said condition or disease isrelated to mucus secretion.44. The method of paragraph 27 wherein said mucus secretion isgastrointestinal.45. The method of paragraph 27 wherein said mucus secretion occurs inthe nose, sinuses, throat, or lungs.46. The method of paragraph 27 wherein said condition or disease isrelated to abdominal cramping.47. The method of paragraph 27 wherein said condition or disease isirritable bowel syndrome.48. The method of paragraph 27 wherein said condition or disease is ableeding disorder.49. The method of paragraph 27 wherein said condition or disease is asleep disorder.50. The method of paragraph 27 wherein said condition or disease ismastocytosis.51. The method of paragraph 27 wherein said condition or disease isassociated with elevated body temperature.52. The method of paragraph 27 wherein said condition or disease isassociated with ocular hypertension and glaucoma.53. The method of paragraph 27 wherein said condition or disease isassociated with ocular hypotension.54. The method of paragraph 27 wherein said condition relates tosurgical procedures to treat pain, inflammation and other unwantedsequelae wherein said surgical procedure includes incision, lasersurgery or implantation.55. The method of paragraph 27 where said condition is related to painand inflammation and post-surgical scar and keloid formation.56. The method of paragraph where said condition is related to diseasesof female reproduction, associated with menstrual cramping,endometriosis, and pre-term labor57 A pharmaceutical product comprising a compound having the followingformula

wherein X is N or CR₇;A is N or CR₇ with the proviso that at least one A is N and when each Ais N, R₂ is absent;Y is (CH₂)_(m) wherein m is 0 or an integer of from 1 to 3;Z is selected from the group consisting of O, S, SO, SO₂ and (CH₂)_(p),wherein p is 0 or an integer of from 1 to 3;W is hydrocarbyl or substituted hydrocarbyl:R₁ is selected from the group consisting of OR₇, N(R₇)₂, and N(R₇)SO₂R₇;R₂ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;R₃ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;R₄ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy; and,R₇ is selected from the group consisting of H, hydrocarbyl andsubstituted hydrocarbyl, e.g. carbocyclic aryl and alkyl or apharmaceutically acceptable salt or a prodrug thereof59. The compound of paragraphs 1-58 wherein the compounds are PGantagonists.60. The compounds of paragraphs 1-58 wherein the compounds are usefulfor treating or reducing the symptoms of a DP₁, FP, EP₁, TP EP1 or EP₄receptor mediated condition or disease and wherein said compound ispackaged and labeled for the treatment or prevention of a disease orcondition selected from the group consisting of uveitis, allergicconditions, asthma, allergic asthma, allergic rhinitis, atherosclerosis,blood coagulation disorders, bone disorders, cancer, cellular neoplastictransformations, chronic obstructive pulmonary diseases and other formsof lung inflammation, congestive heart failure, diabetic retinopathy,diseases or conditions requiring a treatment of anti-coagulation,diseases requiring control of bone formation and resorption,endometriosis fertility disorders, hyperpyrexia, gangrene, glaucoma,hypothermia, immune and autoimmune diseases, inflammatory conditions,menstrual cramping, metastic tumor growth, migraine, mucus secretiondisorders, nasal congestion, nasal inflammation, occlusive vasculardiseases, ocular hypertension, ocular hypotension, osteoporosis, pain,perennial rhinitis, pre-term labor pulmonary congestion, pulmonaryhypotension, Raynaud's disease, rejection in organ transplant andby-pass surgery, respiratory conditions, rheumatoid arthritis,rhinorrhea, shock, sleep disorders, sleep-wake cycle disorders, sportsinjuries, muscle aches and pains, and surgical adjunct for minimizingpain, inflammation and scar/keloid formation.58. A pharmaceutical composition comprising a compound having thefollowing formula

Wherein X is N or CR₇;

A is N or CR₇ with the proviso that at least one A is N and when each Ais N, R₂ is absent;Y is (CH₂)_(m) wherein m is 0 or an integer of from 1 to 3;Z is selected from the group consisting of O, S, SO, SO₂ and (CH₂)_(p),wherein p is 0 or an integer of from 1 to 3;W is hydrocarbyl or substituted hydrocarbyl:R₁ is selected from the group consisting of OR₇, N(R₇)₂, and N(R₇)SO₂R₇;R₂ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;R₃ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;R₄ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy; and,R₇ is selected from the group consisting of H, hydrocarbyl andsubstituted hydrocarbyl, e.g. carbocyclic aryl and alkyl or apharmaceutically acceptable salt or a prodrug thereof, and apharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIGS. 1, 2, 3 and 4 show reaction schemes for the preparation of thecompounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The following terms are used to define the disclosed invention.

“Hydrocarbyl” refers to a hydrocarbon radical having only carbon andhydrogen atoms. Preferably, the hydrocarbyl radical has from 1 to 20carbon atoms, more preferably from 1 to 12 carbon atoms and mostpreferably from 1 to 7 carbon atoms.“Substituted hydrocarbyl” refers to a hydrocarbyl radical wherein one ormore, but not all, of the hydrogen and/or the carbon atoms are replacedby a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radicalincluding a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g.fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.“Alkyl” refers to a straight-chain, branched or cyclic saturatedaliphatic hydrocarbon. Preferably, the alkyl group has 1 to 12 carbons.More preferably, it is an alkyl of from 4 to 10 carbons, most preferably4 to 8 carbons. Typical alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.The alkyl group may be optionally substituted with one or moresubstituents selected from the group consisting of hydroxyl, cyano,alkoxy, ═O, ═S, NO₂, halogen, dimethyl amino, and SH.“Cycloalkyl” refers to a cyclic saturated aliphatic hydrocarbon group.Preferably, the cycloalkyl group has 3 to 12 carbons. More preferably,it has from 4 to 7 carbons, most preferably 5 or 6 carbons.“Aryl” refers to an aromatic group which has at least one ring having aconjugated pi electron system and includes carbocyclic aryl,heterocyclic aryl and biaryl groups. The aryl group may be optionallysubstituted with one or more substituents selected from the groupconsisting of alkyl, hydroxyl, halogen, COOR⁶, NO₂, CF₃, N(R⁶)₂,CON(R⁶)₂, SR⁶, sulfoxy, sulfone, CN and OR⁶, wherein R⁶ is alkyl.“Carbocyclic aryl” refers to an aryl group wherein the ring atoms arecarbon.“Heteroaryl or heterocyclic aryl” refers to an aryl group having from 1to 3 heteroatoms as ring atoms, the remainder of the ring atoms beingcarbon. Heteroatoms include oxygen, sulfur, and nitrogen. Thus,heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl,N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.Preferably, the heteroaryl group has from 2 to 10 carbons. Morepreferably, it has from 3 to 10 carbons, most preferably 3 carbons.Pharmaceutical compositions contemplated herein include compositionswherein the active ingredient is contained in an effective amount, i.e.,in an amount effective to achieve its intended purpose. An “effectiveamount” is an amount sufficient to accomplish a stated purpose (e.g.,achieve the effect for which it is administered, treat a disease, reduceone or more symptoms of a disease or condition). An example of an“effective amount” is an amount sufficient to contribute to thetreatment, prevention, or reduction of a symptom or symptoms of adisease, which can be referred to as a “therapeutically effectiveamount.” A “reduction” of a symptom or symptoms (and grammaticalequivalents of this phrase) means decreasing of the severity orfrequency of the symptom(s), or elimination of the symptom(s). Theactual amount effective for a particular application will depend, interalia, on the condition being treated.“Treatment”, “treat” or “treating” can refer to curing any disease orcondition or reducing or alleviating the symptoms of the disease orcondition.The present invention provides compounds having the general formula I:

wherein X is N or CR₇ independently;A is N or CR₇ with the proviso that at least one A is N and when each Ais N, R₂ is absent;Y is (CH₂)_(m) wherein m is 0 or an integer of from 1 to 3;Z is selected from the group consisting of O, S, SO, SO₂ and (CH₂)_(p),wherein p is 0 or an integer of from 1 to 3;W is hydrocarbyl or substituted hydrocarbyl:R₁ is selected from the group consisting of OR₇, N(R₇)₂, and N(R₇)SO₂R₇;R₂ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;R₃ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;R₄ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy; andR₇ is selected from the group consisting of H, hydrocarbyl andsubstituted hydrocarbyl, e.g. carbocyclic aryl and alkyl.

More preferably, the compound of the invention is represented by theformula II:

Most preferably, the compound of the invention is represented by theformula III:

Preferably, R₁ is OH;

Preferably, R₂ is selected from the group consisting of H, alkyl andhalogen substituted alkyl, e.g. fluoro-substituted alkyl;

Preferably, X is N or CH;

Preferably, R₃ is selected from the group consisting of H, hydroxyl,alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxyl,halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy oraryloxy. More preferably R₃ is chloro or bromo;Preferably, R₄ is selected from the group consisting of H, hydroxyl,alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxyl,halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy oraryloxy. More preferably R₄ is H;Preferably, Y is absent, i.e. n is 0;

Preferably, Z is 0;

Preferably, W is selected from the group consisting of alkyl, aryl,alkoxy, aryloxy and hydroxyl, halogen, nitro, amino andcyano-substituted alkyl, aryl, alkoxy or aryloxy;More preferably W is selected from the group consisting of alkyl, e.g.branched chain alkyl such as 2-ethylbutyl, 2-methylpropyl, etc.The most preferred compounds of the present invention are selected fromthe group consisting of:

-   1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indole-5-carboxylic acid;-   1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic    acid;-   1-(2-Chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;-   1-(2-Bromo-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;-   1-[2-Bromo-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic acid;-   1-[2-Chloro-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylic    acid;-   1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid;-   1-(2-Benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic acid;-   1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic    acid;-   1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(2-Benzyloxy-5-bromo-benzyl)-1H-indazole-5-carboxylic acid;-   1-[5-Bromo-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic    acid;-   1-(5-Bromo-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(5-Bromo-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid;-   2-(5-Bromo-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid;-   1-(2-(Trifluoromethyl)-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(5-Bromo-2-cyclopropyl-2-methylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(5-Bromo-2-isobutoxy-benzyl)-3-methyl-1H-indazole-5-carboxylic    acid;-   1-(2-isobutoxy-5-trifluoromethoxy-benzyl)-3-methyl-1    h-indazole-5-carboxylic acid;-   1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-3-methyl-1    h-indazole-5-carboxylic acid;-   1-(5-chloro-2-isobutoxy-benzyl)-3-methyl-1 h-indazole-5-carboxylic    acid;-   1-(2-isobutoxy-5-trifluoromethyl-benzyl)-3-methyl-1    h-indazole-5-carboxylic acid;-   1-[2-(2-ethyl-butoxy)-5-trifluoromethyl-benzyl]-3-methyl-1    h-indazole-5-carboxylic acid;-   1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-3-methyl-1    h-indazole-5-carboxylic acid;-   1-[5-bromo-2-(1-methyl-cyclopropylmethoxy)-benzyl]-3-methyl-1    h-indazole-5-carboxylic acid;-   1-[5-chloro-2-(1-methyl-cyclopropylmethoxy)-benzyl]-3-methyl-1    h-indazole-5-carboxylic acid;-   1-(5-Bromo-2-isobutoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic    acid;-   1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic    acid;-   1-[2-(4-Chloro-benzyloxy)-5-trifluoromethyl-benzyl]-1H-indazole-5-carboxylic    acid;-   1-(2-Cyclopentylmethoxy-5-trifluoromethyl-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-4-carboxylic    acid;-   2-(5-Chloro-2-cyclopropylmethoxy-benzyl)-2H-indazole-4-carboxylic    acid;-   1-(5-Chloro-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid;-   2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-4-carboxylic acid;-   1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-4-carboxylic    acid;-   2-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-2H-indazole-4-carboxylic    acid;-   1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-4-carboxylic    acid;-   2-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-2H-indazole-4-carboxylic    acid;-   1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-6-carboxylic acid;-   2-(5-Bromo-2-isobutoxy-benzyl)-2H-indazole-6-carboxylic acid;-   1-(5-Bromo-2-cyclopentylmethoxy-benzyl)-1H-indazole-6-carboxylic    acid;-   2-(5-Bromo-2-cyclopentylmethoxy-benzyl)-2H-indazole-6-carboxylic    acid;-   1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylic    acid;-   1-(5-Chloro-3-fluoro-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(2-Isobutoxy-5-methanesulfonyl-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(4,5-Dichloro-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;-   1-(3-Isobutoxy-6-methyl-pyridin-2-ylmethyl)-1H-indazole-5-carboxylic    acid;-   1-[5-Bromo-2-(1-ethyl-propoxy)-benzyl]-1H-indazole-5-carboxylic    acid;-   1-[5-Bromo-2-(2,2-dimethyl-propoxy)-benzyl]-1H-indazole-5-carboxylic    acid;-   1-[5-Bromo-2-(2-hydroxy-2-methyl-propoxy)-benzyl]-1H-indazole-5-carboxylic    acid;-   1-(5-Hydroxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;-   1-[5-(2,2-Difluoro-ethoxy)-2-isobutoxy-benzyl]-1H-indazole-5-carboxylic    acid;-   1-(5-Difluoromethoxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(5-Chloro-2-isobutoxy-benzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic    acid;-   1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic    acid;-   1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic    acid;-   1-[5-CHLORO-2-(2-ethyl-butoxy)-benzyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic    acid;-   1-(5-Chloro-2-isobutoxy-benzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic    acid;-   1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazolo[3,4-c]pyridine-5-carboxylic    acid amide;-   1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazolo[3,4-c]pyridine-5-carboxylic    acid;-   1-(5-bromo-2-isobutoxy-benzyl)-3-ethyl-1 h-indazole-5-carboxylic    acid;-   1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-3-ethyl-1h-indazole-5-carboxylic    acid;-   1-(5-bromo-2-isobutoxy-benzyl)-2-methyl-1h-indole-5-carboxylic acid;-   1-(5-bromo-2-isobutoxy-benzyl)-1h-indole-5-carboxylic acid;-   1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-2-methyl-1h-indole-5-carboxylic    acid;-   1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-indole-5-carboxylic acid;-   1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-indole-6-carboxylic acid;-   1-(2-isobutoxy-5-trifluoromethoxy-benzyl)-1h-indole-5-carboxylic    acid;-   1-(5-bromo-2-isobutoxy-benzyl)-1h-pyrrolo[2,3-b]pyridine-5-carboxylic    acid;-   1-(5-bromo-2-isobutoxy-benzyl)-1h-pyrrolo[3,2-b]pyridine-5-carboxylic    acid;-   1-(2-isobutoxy-5-trifluoromethoxy-benzyl)-1h-pyrrolo[2,3-b]pyridine-5-carboxylic    acid;-   1-(2-isobutoxy-5-trifluoromethoxy-benzyl)-3-methyl-1h-indole-5-carboxylic    acid;-   1-[2-(2-ethyl-butoxy)-5-trifluoromethoxy-benzyl]-1h-pyrrolo[2,3-b]pyridine-5-carboxylic    acid;-   1-[2-(2-ethyl-butoxy)-5-trifluoromethoxy-benzyl]-3-methyl-1h-indole-5-carboxylic    acid;-   1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-benzoimidazole-5-carboxylic    acid;-   1-(5-bromo-2-isobutoxy-benzyl)-1h-benzoimidazole-5-carboxylic acid;-   1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic    acid;-   1-(2-Chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;-   1-(2-Bromo-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;-   1-[2-Bromo-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic acid;-   1-[2-Chloro-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylic    acid;-   1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid;-   1-(2-Benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic acid;-   1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic    acid;-   1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(2-Benzyloxy-5-bromo-benzyl)-1H-indazole-5-carboxylic acid;-   1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic    acid;-   1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(5-Bromo-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid;-   2-(5-Bromo-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid;-   1-(2-(Trifluoromethyl)-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(5-Bromo-2-cyclopropyl-2-methylmethoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylic    acid;-   1-(5-Bromo-2-isobutoxy-benzyl)-3-methyl-1H-indazole-5-carboxylic    acid;-   1-(5-Bromo-2-isobutoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic    acid; and,-   1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic    acid.

As shown in FIGS. 1, 2, 3 and 4, the compounds of the present inventionmay be prepared by the methods disclosed in the Examples.

The following examples are intended to illustrate the present invention.The reagents and conditions used in FIGS. 1, 2, 3 and 4 and the examplesmay be abbreviated as follows:Ac is acetyl;DCM is dichloromethane;DTAD is Di-tert-butyl azodicarboxylate;TFA is trifluoroacetic acid;RT is room temperature;Ph is phenyl;DiBAL-His diisobutylaluminumhydride;DMF is dimethylformamide;Et is ethyl;THF is tetrahydrofuran;DMAP is 4-dimethylaminopyridine;HEPES is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid).

Example 1 1-[5-Chloro-2-(2-Ethyl-Butoxy)-Benzyl]-1H-Indole-5-CarboxylicAcid

Step 1 2-Bromomethyl-1-chloro-4-(2-ethyl-butoxy)-benzene 1

To a solution of 4-chloro-2-methylphenol 5 g (35 mmol) in DMF (75 mL)were added potassium carbonate 10 g (70 mmol), tetrabutylammonium iodide0.5 g (1.4 mmol) and 3-chloromethylpentane 7.7 ml (52.6 mmol). Theresulting mixture was refluxed for 20 hours. The mixture was poured into2M NaOH solution and extracted with EtOAC. The organic layers werecombined, washed with aqueous HCl and with brine, dried (MgSO₄) and thevolatiles were removed in vacuo. The crude product (5.1 g) was usedwithout further purification. LC-MS: m/z 227 M+H⁺.

A solution of 1-chloro-4-(2-ethyl-butoxy)-2-methyl-benzene (5.1 g, 22.5mmol), N-bromosuccinimide (4.8 g, 27 mmol) and benzoylperoxide (0.27 g,1.1 mmol) in CCl₄ (50 mL) was refluxed under illumination from a highenergy lamp for 3 hours. The reaction mixture was cooled to roomtemperature and partitioned between water (50 mL) and CH₂Cl₂ (25 mL).The aqueous layer was extracted with CH₂Cl₂ (25 mL). The combinedorganic layers were washed with water (2×75 mL), dried (Na₂SO₄) andevaporated to dryness to give bromide 1 as a light brown oil, 3.9 g(57%).

¹H-NMR (CDCl₃, 300 MHz) δ7.25 (m, 2H, ArH), 6.80 (dd, 1H, ArH), 4.50 (s,2H, ArCH), 3.93 (dd, 2H, CH₂), 1.73 (m, 1H, —CH), 1.54 (m, 4H, —CH₂),0.94 (m, 6H —CH₃). LC-MS: m/z 306 M+H⁺

Step 2 1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1h-indole-5-carboxylicacid methyl ester 2

To a solution of 2-bromomethyl-1-chloro-4-(2-ethyl-butoxy)-benzene 10.11 g (0.63 mmol) in DMF (2.5 mL) were added potassium carbonate 0.24 g(1.74 mmol), tetrabutylammonium iodide 0.02 g and methylindole-5-carboxylate 0.22 g (1.26 mmol). The resulting mixture washeated at 150° C. in an Emrys microwave reactor for 20 minutes. Themixture was poured into water and extracted with EtOAc. The organiclayers were combined, washed with aqueous HCl (20 ml, 2M) and with brine(20 mL), dried (MgSO₄) and the volatiles were removed in vacuo. Thecrude product was purified on silica to yield1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indole-5-carboxylic acidmethyl ester 2 0.04 g as a white solid (16%).

¹H-NMR (CDCl₃, 300 MHz) δ 8.43 (d, 1H, ArH), 7.91 (dd, 1H, ArH), 7.32(d, 1H, ArH), 7.19 (dd, 2H, ArH), 6.85 (d, 1H, ArH), 6.70 (dd, 1H, ArH),6.66 (dd, 1H, ArH), 5.31 (s, 2H, ArCH₂), 3.95 (s, 2H, CH₃), 3.94 (dd,2H, CH₂) 1.70 (m, 1H, CH), 1.47 (m, 4H, CH₂), 0.95 (m, 6H, CH₃). LC-MS:m/z 400 M+H⁺.

Step 3 1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indole-5-carboxylicacid 3

To a solution of1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indole-5-carboxylic acidmethyl ester 2 0.04 g (0.1 mmol) in a mixture of THF (2 mL) and methanol(1 ml) was added a solution of LiOH (0.12 g in 0.7 ml H₂O). Theresulting mixture was heated at 100° C. in an Emrys microwave reactorfor 10 minutes. The mixture was poured into water (20 mL) and extractedwith EtOAc (3×15 mL). The organic layers were combined, washed withbrine (30 mL), dried (MgSO₄) and the volatiles were removed in vacuo.The crude product was purified on silica to yield 21.9 mg (57%) of1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indole-5-carboxylic acid 3 asa white solid.

¹H-NMR (CDCl₃, 8.54 (s, 1H, ArH), 7.99 (dd, 1H, ArH), 7.37 (dd, 1H,ArH), 7.20 (dd, 2H, ArH), 6.86 (d, 1H, ArH), 6.74 (dd, 1H, ArH), 6.70(dd, 1H, ArH), 5.33 (s, 2H, ArCH₂), 3.92 (dd, 2H, CH₂) 1.70 (m, 1H, CH),1.47 (m, 4H, CH₂), 0.95 (m, 6H, CH₃). LC-MS: m/z 386 M+H⁺.

Example 21-[5-Chloro-2-(2-Ethyl-Butoxy)-Benzyl]-1H-Indazole-5-Carboxylic Acid 6

Step 1 1H-Indazole-5-carboxylic acid methyl ester 4

A solution of 1H-indazole-5-carboxylic acid 0.25 g (1.54 mmol) inmethanol (2.5 mL) and conc. H₂SO₄ (0.1 ml) was heated at 100° C. in anEmrys microwave reactor for 5 minutes. The mixture was poured into water(20 mL) and extracted with EtOAc (3×15 mL). The organic layers werecombined, washed with saturated NaHCO₃ and brine (30 mL), dried (MgSO₄)and the volatiles were removed in vacuo to yield of1H-indazole-5-carboxylic acid methyl ester 0.086 g (32%) 4 as a paleyellow solid.

¹H-NMR (CDCl₃, δ 8.58 (dd, 1H, ArH), 8.21 (d, 1H, ArH), 8.11 (dd, 1H,ArH), 7.54 (d, 2H, ArH), 3.98 (s, 3H, CH₃).

LC-MS: m/z 177 M+H⁺.

Step 2 1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylicacid methyl ester, 5

The title compound was prepared following the method in Example 1, Step2.

¹H-NMR (CDCl₃, 300 MHz) δ 8.55 (dd, 1H, ArH), 8.18 (d, 1H, ArH), 8.05(dd, 1H, ArH), 7.40 (d, 1H, ArH), 7.20 (dd, 1H, ArH), 6.84 (d, 1H, ArH),6.80 (dd, 1H, ArH), 5.60 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃), 3.91 (dd,2H, CH₂) 1.70 (m, 1H, CH), 1.47 (m, 4H, CH₂), 0.94 (m, 6H, CH₃). LC-MS:m/z 401 M+H⁺.

Step 3 1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylicacid, 6

The title compound was prepared following the method in Example 1, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.66 (dd, 1H, ArH), 8.22 (d, 1H, ArH), 8.11(dd, 1H, ArH), 7.45 (d, 1H, ArH), 7.21 (dd, 1H, ArH), 6.85 (dd, 1H,ArH), 6.83 (d, 1H, ArH), 5.62 (s, 2H, ArCH₂), 3.91 (d, 2H, CH₂) 1.70 (m,1H, CH), 1.47 (m, 4H, CH₂), 0.95 (m, 6H, CH₃).

LC-MS: m/z 387 M+H⁺.

Example 3 1-(2-Chloro-5-Isobutoxy-Benzyl)-1H-Indazole-5-Carboxylic Acid,10

Step 1 1-(5-Chloro-2-methoxy-benzyl)-1H-indazole-5-carboxylic acidmethyl ester, 7

A solution of 1H-indazole-5-carboxylic acid methyl ester, 4, (0.05 g0.28 mmol), triphenylphosphine (0.11 g, 0.43 mmol),di-tert-butylazodicarboxylate (0.1 g, 0.43 mmol) and(5-chloro-2-methoxy-phenyl)-methanol, (0.075 g, 0.43 mmol) in a mixtureof THF (1 mL) and toluene (1 ml) was heated at 120° C. in an Emrysmicrowave reactor for 20 min. The volatiles were removed in vacuo. Thecrude product was purified on silica to yield1-(5-chloro-2-methoxy-benzyl)-1H-indazole-5-carboxylic acid methylester, 7. 0.035 g (38%).

¹H-NMR (CDCl₃, 300 MHz) δ 8.54 (s, 1H, ArH), 8.17 (s, 1H, ArH), 8.07(dd, 1H, ArH), 7.47 (dd, 1H, ArH), 7.22 (dd, 1H, ArH), 6.90 (d, 1H,ArH), 6.83 (dd, 1H, ArH), 5.59 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃), 3.86(s, 3H, CH₃).

Step 2 1-(2-Chloro-5-hydroxy-benzyl)-1H-indazole-5-carboxylic acidmethyl ester, 8

To a solution of 1-(5-chloro-2-methoxy-benzyl)-1H-indazole-5-carboxylicacid methyl ester, 8, 0.09 g (0.27 mmol) in dry DCM (10 ml) under N₂ atmat 0° C., 2.0 ml of boron tribromide (1M in DCM) was added. and thesolution was allowed to warm to room temperature. The mixture wasstirred for 24 hours, quenched with MeOH and refluxed for 3 hours. Aftercooling to room temperature, water was added and the mixture wasextracted with EtOAc and washed with brine. After drying over MgSO₄, thesolvents were removed in vacuo to yield 0.05 g of1-(2-chloro-5-hydroxy-benzyl)-1H-indazole-5-carboxylic acid methylester, 8.

¹H-NMR (CDCl₃, 300 MHz) δ 8.36 (s, 1H, ArH), 8.13 (s, 1H, ArH), 7.84 (m,2H, ArH), 7.28 (d, 1H, ArH), 7.19 (dd, 1H, ArH), 6.93 (d, 1H, ArH), 5.52(s, 2H, ArCH₂), 4.03 (s, 3H, CH₃).

LC-MS: m/z 317 M+H⁺.

Step 3 1-(2-Chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acidmethyl ester, 9

A solution of 1-(2-Chloro-5-hydroxy-benzyl)-1H-indazole-5-carboxylicacid methyl ester 8 (0.1 g g 0.33 mmol), triphenylphosphine (0.173 g,0.66 mmol), di-tert-butylazodicarboxylate (0.15 g, 0.66 mmol) and2-methyl-1-propanol (0.061 mL, 0.66 mmol) in THF (3 mL) was at 120° C.on microwave for 20 min. The volatiles were removed in vacuo. The crudeproduct was purified on silica to yield1-(2-chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid methylester, 9.

0.09 g (73%).

¹H-NMR (CDCl₃, 300 MHz) δ8.55 (s, 1H, ArH), 8.18 (s, 1H, ArH), 8.05 (dd,1H, ArH), 7.43 (d, 1H, ArH), 7.20 (dd, 1H, ArH), 6.83 (s, 1H, ArH), 6.81(d, 1H, ArH), 5.62 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃), 3.77 (d, 2H, CH₂).2.11 (m, 1H, CH), 1.04 (d, 6H, CH₃).

LC-MS: m/z 373 M+H⁺.

Step 4 1-(2-Chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid, 10

The title compound was prepared following the method in Example 1, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.64 (s, 1H, ArH), 8.22 (s, 1H, ArH), 8.11(dd, 1H, ArH), 7.47 (d, 1H, ArH), 7.21 (dd, 1H, ArH), 6.86 (d, 1H, ArH),6.82 (d, 1H, ArH), 5.63 (s, 2H, ArCH₂), 3.78 (d, 2H, CH₂). 2.10 (m, 1H,CH), 1.04 (d, 6H, CH₃).

LC-MS: m/z 359 M+H⁺.

Example 4 1-(2-Bromo-5-Isobutoxy-Benzyl)-1H-Indazole-5-Carboxylic Acid,14

Step 1 1-(5-Bromo-2-methoxy-benzyl)-1H-indazole-5-carboxylic acid methylester, 11

The title compound was prepared following the method in Example 3,Step 1. But using (5-bromo-2-methoxy-phenyl)-methanol, instead of(5-chloro-2-methoxy-phenyl)-methanol,

¹H-NMR (CDCl₃, 300 MHz) δ 8.54 (s, 1H, ArH), 8.17 (s, 1H, ArH), 8.07(dd, 1H, ArH), 7.47 (dd, 1H, ArH), 7.22 (dd, 1H, ArH), 6.90 (d, 1H,ArH), 6.83 (dd, 1H, ArH), 5.59 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃), 3.86(s, 3H, CH₃).

LC-MS: m/z 376 M+H⁺.

Step 2 1-(2-Bromo-5-hydroxy-benzyl)-1H-indazole-5-carboxylic acid methylester, 12

The title compound was prepared following the method in Example 3, Step2.

¹H-NMR (CDCl₃, 300 MHz) δ 8.56 (s, 1H, ArH), 8.18 (dd, 1H, ArH), 8.16(dd, 1H, ArH), 7.58 (d, 1H, ArH), 7.42 (d, 1H, ArH), 7.35 (dd, 1H, ArH),6.90 (d, 1H, ArH), 5.47 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃).

LC-MS: m/z 362 M+H⁺.

Step 3 1-(2-Bromo-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acidmethyl ester, 13

The title compound was prepared following the method in Example 3, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.17 (s, 1H, ArH), 8.06(dd, 1H, ArH), 7.43 (d, 1H, ArH), 7.35 (dd, 1H, ArH), 6.99 (d, 1H, ArH),6.76 (d, 1H, ArH), 5.61 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃), 3.76 (d, 2H,CH₂). 2.11 (m, 1H, CH), 1.03 (d, 6H, CH₃).

LC-MS: m/z 418 M+H⁺.

Step 4 1-(2-Bromo-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid, 14

The title compound was prepared following the method in Example 1, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.65 (s, 1H, ArH), 8.21 (s, 1H, ArH), 8.11(dd, 1H, ArH), 7.48 (d, 1H, ArH), 7.36 (dd, 1H, ArH), 7.02 (d, 1H, ArH),6.77 (d, 1H, ArH), 5.63 (s, 2H, ArCH₂), 3.77 (d, 2H, CH₂). 2.11 (m, 1H,CH), 1.03 (d, 6H, CH₃), LC-MS: m/z 404 M+H⁺.

Example 5 1-[2-Bromo-5-(2-Ethyl-Butoxy)-Benzyl]-1H-Indazole-5-CarboxylicAcid, 16

Step 1 1-[2-Bromo-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylicacid methyl ester, 15

The title compound was prepared following the method in Example 3, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.18 (s, 1H, ArH), 8.05(dd, 1H, ArH), 7.41 (d, 1H, ArH), 7.35 (dd, 1H, ArH), 6.95 (d, 1H, ArH),6.80 (d, 1H, ArH), 5.60 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃), 3.90 (d, 2H,CH₂). 1.69 (m, 1H, CH), 1.46 (m, 4H, CH₂), 0.94 (t, 6H, CH₃).

LC-MS: m/z 446 M+H⁺.

Step 2

1-[2-Bromo-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic acid, 16

The title compound was prepared following the method in Example 1, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.65 (s, 1H, ArH), 8.22 (s, 1H, ArH), 8.11(dd, 1H, ArH), 7.45 (d, 1H, ArH), 7.36 (dd, 1H, ArH), 6.99 (d, 1H, ArH),6.80 (d, 1H, ArH), 5.62 (s, 2H, ArCH₂), 3.92 (s, 3H, CH₃), 3.90 (d, 2H,CH₂). 1.69 (m, 1H, CH), 1.46 (m, 4H, CH₂), 0.94 (t, 6H, CH₃).

LC-MS: m/z 446 M+H⁺.

Example 61-[2-Chloro-5-(2-Ethyl-Butoxy)-Benzyl]-1H-Indazole-6-Carboxylic Acid, 21

Step 1 1H-Indazole-6-carboxylic acid methyl ester 17

The title compound was prepared following the method in Example 2, Step1.

¹H-NMR (CDCl₃, δ 10.37 (broad s, 1H, —NH), 8.29 (s, 1H, ArH), 8.17 (s,1H, ArH), 8.11 (dd, 1H, ArH), 7.85 (dd, 2H, ArH), 3.99 (s, 3H, CH₃).

LC-MS: m/z 177 M+H⁺.

Step 2 1-(2-Chloro-5-methoxy-benzyl)-1H-indazole-6-carboxylic acidmethyl ester, 18

The title compound was prepared following the method in Example 3, Step1.

¹H-NMR (CDCl₃, 300 MHz) δ 8.27 (s, 1H, ArH), 8.11 (s, 1H, ArH), 7.80 (m,2H, ArH), 7.20 (dd, 1H, ArH), 6.89 (dd, 1H, ArH), 6.82 (d, 1H, ArH),5.63 (s, 2H, ArCH₂), 3.96 (s, 3H, CH₃), 3.89 (s, 3H, CH₃).

LC-MS: m/z 331 M+H⁺.

Step 3 1-(2-Chloro-5-hydroxy-benzyl)-1H-indazole-6-carboxylic methylester, 19

The title compound was prepared following the method in Example 3, Step2.

¹H-NMR (CDCl₃, 300 MHz) δ 8.33 (s, 1H, ArH), 8.13 (s, 1H, ArH), 7.84 (m,2H, ArH), 7.29 (d, 1H, ArH), 7.19 (dd, 1H, ArH), 6.94 (d, 1H, ArH), 5.52(s, 2H, ArCH₂), 4.03 (s, 3H, CH₃).

LC-MS: m/z 331 M+H⁺.

Step 4 1-[2-Chloro-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylicacid methyl ester 20

The title compound was prepared following the method in Example 3, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.18 (s, 1H, ArH), 8.13 (s, 1H, ArH), 7.83 (m,2H, ArH), 7.20 (dd, 1H, ArH), 6.84 (d, 1H, ArH), 6.72 (d, 1H, ArH), 5.65(s, 2H, ArCH₂), 3.97 (s, 3H, CH₃), 3.92 (d, 2H, CH₂). 1.73 (m, 1H, CH),1.48 (m, 4H, CH₂), 0.95 (t, 6H, CH₃).

LC-MS: m/z 401 M+H⁺.

Step 5 1-[2-Chloro-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylicacid, 21

The title compound was prepared following the method in Example 1, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.29 (s, 1H, ArH), 8.16 (s, 1H, ArH), 7.88 (m,2H, ArH), 7.21 (dd, 1H, ArH), 6.85 (d, 1H, ArH), 6.82 (d, 1H, ArH), 5.68(s, 2H, ArCH₂), 3.93 (d, 2H, CH₂). 1.76 (m, 1H, CH), 1.48 (m, 4H, CH₂),0.95 (t, 6H, CH₃).

LC-MS: m/z 387 M+H⁺.

Example 7 1-(5-Bromo-2-Isobutoxy-Benzyl)-1H-Indazole-4-Carboxylic Acid,25

Step 1 1-(5-Bromo-2-methoxy-benzyl)-1H-indazole-4-carboxylic acid methylester, 22

The title compound was prepared following the method in Example 3, Step1.

¹H-NMR (CDCl₃, 300 MHz) δ 8.56 (s, 1H, ArH), 7.94 (d, 1H, ArH), 7.65 (d,1H, ArH), 7.44 (dd, 1H, ArH), 6.98 (d, 1H, ArH), 6.76 (m, 2H, ArH), 5.61(s, 2H, ArCH₂), 4.04 (s, 3H, CH₃), 3.85 (s, 3H, CH₃).

LC-MS: m/z 376 M+H⁺.

Step 2 1-(5-Bromo-2-hydroxy-benzyl)-1H-indazole-4-carboxylic acid methylester, 23

The title compound was prepared following the method in Example 3, Step2.

¹H-NMR (CDCl₃, 300 MHz) δ 9.48 (s, 1H, ArOH), 8.59 (s, 1H, ArH), 7.98(d, 1H, ArH), 7.78 (d, 1H, ArH), 7.56 (dd, 1H, ArH), 7.39 (d, 1H, ArH),7.33 (dd, 1H, ArH), 6.89 (d, 1H, ArH), 5.49 (s, 2H, ArCH₂), 4.03 (s, 3H,CH₃).

LC-MS: m/z 362 M+H⁺.

Step 3 1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acidmethyl ester, 24

The title compound was prepared following the method in Example 3, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.58 (s, 1H, ArH), 7.96 (d, 1H, ArH), 7.63 (d,1H, ArH), 7.43 (dd, 1H, ArH), 7.33 (dd, 1H, ArH), 6.91 (d, 1H, ArH),6.76 (d, 1H, ArH), 5.65 (s, 2H, ArCH₂), 4.05 (s, 3H, CH₃), 3.76 (d, 2H,CH₂). 2.12 (m, 1H, CH), 1.05 (d, 6H, CH₃).

LC-MS: m/z 418 M+H⁺.

Step 4 1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid, 25

The title compound was prepared following the method in Example 1, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.67 (s, 1H, ArH), 8.07 (d, 1H, ArH), 7.71 (d,1H, ArH), 7.48 (dd, 1H, ArH), 7.34 (dd, 1H, ArH), 6.97 (d, 1H, ArH),6.77 (d, 1H, ArH), 5.68 (s, 2H, ArCH₂), 3.78 (d, 2H, CH₂). 2.12 (m, 1H,CH), 1.05 (d, 6H, CH₃).

LC-MS: m/z 404 M+H⁺.

Example 8 1-(2-Benzyloxy-5-Chloro-Benzyl)-1H-Indazole-5-Carboxylic Acid,27

Step 1 1-(2-Benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic acidmethyl ester, 26

To a solution of 1-(5-Chloro-2-hydroxy-benzyl)-1H-indazole-5-carboxylicacid methyl ester, 8, 0.04 g (0.13 mmol) in acetonitrile (10 ml), benzylbromide (0.026 g, 0.15 mmol) and K₂CO₃ (0.026 g, 0.19 mmol) was added.The mixture was stirred under reflux for 2 hours, then the solids werefiltered off and the solvents were removed in vacuo. The crude productwas purified on silica to yield 0.05 g of1-(2-benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic acid methylester, 28 as a white solid.

H-NMR (CDCl₃, 300 MHz) δ 8.52 (s, 1H, ArH), 8.16 (s, 1H, ArH), 7.92 (dd,1H, ArH), 7.44-7.25 (m, 6H, ArH), 7.21 (dd, 1H, ArH), 6.96 (d, 1H, ArH),6.89 (d, 1H, ArH), 5.61 (s, 2H, ArCH₂), 5.09 (s, 2H, ArCH₂), 3.97 (s,3H, CH₃).

LC-MS: m/z 407 M+H⁺.

Step 2 1-(2-Benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic acid, 27

The title compound was prepared following the method in Example 1, Step3.

H-NMR (CDCl₃, 300 MHz) δ 8.62 (s, 1H, ArH), 8.20 (s, 1H, ArH), 7.96 (dd,1H, ArH), 7.45-7.30 (m, 6H, ArH), 7.22 (dd, 1H, ArH), 7.01 (d, 1H, ArH),6.91 (d, 1H, ArH), 5.62 (s, 2H, ArCH₂), 5.08 (s, 2H, ArCH₂), 3.97 (s,3H, CH₃).

LC-MS: m/z 407 M+H⁺.

Example 91-[5-Chloro-2-(4-Chloro-Benzyloxy)-Benzyl]-1H-Indazole-5-CarboxylicAcid, 29

Step 11-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic acidmethyl ester, 28

The title compound was prepared following the method in Example 8, Step1.

H-NMR (CDCl₃, 300 MHz) δ 8.52 (s, 1H, ArH), 8.15 (s, 1H, ArH), 7.93 (dd,1H, ArH), 7.38-7.17 (m, 6H, ArH), 6.98 (d, 1H, ArH), 6.85 (d, 1H, ArH),5.58 (s, 2H, ArCH₂), 5.01 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃).

LC-MS: m/z 442 M+H⁺.

Step 21-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylicacid, 29

The title compound was prepared following the method in Example 1, Step3.

H-NMR (CDCl₃, 300 MHz) δ 8.63 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.00 (dd,1H, ArH), 7.40-7.31 (m, 3H, ArH), 7.30-7.18 (m, 3H, ArH), 7.01 (d, 1H,ArH), 6.87 (d, 1H, ArH), 5.61 (s, 2H, ArCH₂), 5.04 (s, 2H, ArCH₂).

LC-MS: m/z 428 M+H⁺.

Example 101-(5-Chloro-2-Cyclopentylmethoxy-Benzyl)-1H-Indazole-5-Carboxylic Acid,31

Step 1 1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylicacid methyl ester, 30

The title compound was prepared following the method in Example 3, Step3.

H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.17 (s, 1H, ArH), 8.06 (dd,1H, ArH), 7.45 (dd, 1H, ArH), 7.19 (dd, 1H, ArH), 6.86 (d, 1H, ArH),6.81 (d, 1H, ArH), 5.30 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃), 3.87 (d, 2H,CH₂), 2.37 (m, 1H, CH), 1.92-0.81 (m, 8H, CH₂).

LC-MS: m/z 399 M+H⁺.

Step 2 1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylicacid, 31

The title compound was prepared following the method in Example 1, Step3.

H-NMR (CDCl₃, 300 MHz) δ 8.66 (s, 1H, ArH), 8.22 (s, 1H, ArH), 8.12 (dd,1H, ArH), 7.50 (d, 1H, ArH), 7.21 (d, 1H, ArH), 6.91 (d, 1H, ArH), 6.82(d, 1H, ArH), 5.62 (s, 2H, ArCH₂), 3.88 (d, 2H, CH₂), 2.37 (m, 1H, CH),1.83 (m, 2H, CH₂), 1.64 (m, 4H, CH₂), 1.45-1.21 (m, 2H, CH₂).

LC-MS: m/z 385 M+H⁺.

Example 111-(5-Chloro-2-Cyclopropylmethoxy-Benzyl)-1H-Indazole-5-Carboxylic Acid,33

Step 1 1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylicacid methyl ester, 32

The title compound was prepared following the method in Example 3, Step3 and was used without purification in subsequent step.

LC-MS: m/z 371 M+H⁺.

Step 2 1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylicacid, 33

The title compound was prepared following the method in Example 1, Step3.

H-NMR (CDCl₃, 300 MHz) δ 8.63 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.11 (dd,1H, ArH), 7.63 (d, 1H, ArH), 7.20 (d, 1H, ArH), 7.06 (d, 1H, ArH), 6.77(d, 1H, ArH), 5.64 (s, 2H, ArCH₂), 3.82 (d, 2H, CH₂), 1.24 (m, 1H, CH),0.65 (m, 2H, CH₂), 0.33 (m, 2H, CH₂).

LC-MS: m/z 357 M+H⁺.

Example 12 1-(2-Benzyloxy-5-Bromo-Benzyl)-1H-Indazole-5-Carboxylic Acid,35

Step 1 1-(2-Benzyloxy-5-bromo-benzyl)-1H-indazole-5-carboxylic acidmethyl ester, 34

The title compound was prepared following the method in Example 8, Step1.

H-NMR (CDCl₃, 300 MHz) δ 8.52 (s, 1H, ArH), 8.16 (s, 1H, ArH), 7.91 (dd,1H, ArH), 7.44-7.25 (m, 7H, ArH), 7.12 (dd, 1H, ArH), 6.84 (d, 1H, ArH),5.60 (s, 2H, ArCH₂), 5.08 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃).

LC-MS: m/z 452 M+H⁺.

Step 2 1-(2-Benzyloxy-5-bromo-benzyl)-1H-indazole-5-carboxylic acid, 35

The title compound was prepared following the method in Example 1, Step3.

H-NMR (CDCl₃, 300 MHz) δ 8.60 (s, 1H, ArH), 8.19 (s, 1H, ArH), 7.95 (dd,1H, ArH), 7.43-7.29 (m, 7H, ArH), 7.17 (dd, 1H, ArH), 6.85 (d, 1H, ArH),5.61 (s, 2H, ArCH₂), 5.08 (s, 2H, ArCH₂).

LC-MS: m/z 438 M+H⁺.

Example 131-[5-Bromo-2-(4-Chloro-Benzyloxy)-Benzyl]-1H-Indazole-5-Carboxylic Acid,37

Step 11-[5-Bromo-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic acidmethyl ester, 36

The title compound was prepared following the method in Example 8, Step1.

H-NMR (CDCl₃, 300 MHz) 8.52 (s, 1H, ArH), 8.15 (s, 1H, ArH), 7.93 (dd,1H, ArH), 7.42-7.17 (m, 6H, ArH), 7.14 (d, 1H, ArH), 6.80 (d, 1H, ArH),5.58 (s, 2H, ArCH₂), 5.02 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃).

LC-MS: m/z 486 M+H⁺.

Step 21-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylicacid, 37

The title compound was prepared following the method in Example 1, Step3.

H-NMR (CDCl₃, 300 MHz) δ 8.63 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.00 (dd,1H, ArH), 7.43-7.17 (m, 6H, ArH), 7.17 (d, 1H, ArH), 6.82 (d, 1H, ArH),5.60 (s, 2H, ArCH₂), 5.03 (s, 2H, ArCH₂).

LC-MS: m/z 428 M+H⁺.

Example 141-(5-Bromo-2-Cyclopentylmethoxy-Benzyl)-1H-Indazole-5-Carboxylic Acid,39

Step 1 1-(5-Bromo-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylicacid methyl ester, 38

The title compound was prepared following the method in Example 3, Step3.

H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.17 (s, 1H, ArH), 8.05 (dd,1H, ArH), 7.46 (dd, 1H, ArH), 7.34 (dd, 1H, ArH), 7.02 (d, 1H, ArH),6.77 (d, 1H, ArH), 5.59 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃), 3.87 (d, 2H,CH₂), 2.36 (m, 1H, CH), 1.91-0.81 (m, 8H, CH₂).

LC-MS: m/z 444 M+H⁺.

Step 2 1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylicacid, 39

The title compound was prepared following the method in Example 1, Step3.

H-NMR (CDCl₃, 300 MHz) δ 8.65 (s, 1H, ArH), 8.21 (s, 1H, ArH), 8.11 (dd,1H, ArH), 7.50 (d, 1H, ArH), 7.35 (d, 1H, ArH), 7.06 (d, 1H, ArH), 6.78(d, 1H, ArH), 5.61 (s, 2H, ArCH₂), 3.87 (d, 2H, CH₂), 2.36 (m, 1H, CH),1.83 (m, 2H, CH₂), 1.91-1.17 (m, 8H, CH₂).

LC-MS: m/z 430 M+H⁺.

Example 151-(5-Bromo-2-Cyclopropylmethoxy-Benzyl)-1H-Indazole-5-Carboxylic Acid,41

Step 1 1-(5-Bromo-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylicacid methyl ester, 40

The title compound was prepared following the method in Example 3, Step3.

H-NMR (CDCl₃, 300 MHz) δ 8.53 (s, 1H, ArH), 8.16 (s, 1H, ArH), 8.05 (dd,1H, ArH), 7.59 (d, 1H, ArH), 7.34 (dd, 1H, ArH), 7.18 (d, 1H, ArH), 6.71(d, 1H, ArH), 5.61 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃), 3.81 (d, 2H, CH₂),1.23 (m, 1H, CH), 0.92 (m, 2H, CH₂), 0.63 (m, 2H, CH₂).

LC-MS: m/z 416 M+H⁺.

Step 2 1-(5-Bromo-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylicacid, 41

The title compound was prepared following the method in Example 1, Step3.

H-NMR (CDCl₃, 300 MHz) δ 8.61 (s, 1H, ArH), 8.19 (s, 1H, ArH), 8.09 (dd,1H, ArH), 7.63 (d, 1H, ArH), 7.35 (dd, 1H, ArH), 7.21 (d, 1H, ArH), 6.72(d, 1H, ArH), 5.63 (s, 2H, ArCH₂), 3.81 (d, 2H, CH₂), 1.26 (m, 1H, CH),0.64 (m, 2H, CH₂), 0.32 (m, 2H, CH₂).

LC-MS: m/z 402 M+H⁺.

Example 16 2-(5-Chloro-2-Isobutoxy-Benzyl)-2H-Indazole-5-CarboxylicAcid, 45

Step 1 2-(5-Chloro-2-methoxy-benzyl)-2H-indazole-5-carboxylic acidmethyl ester 42

The title compound was prepared following the method in Example 3, Step1.

¹H-NMR (CDCl₃, 300 MHz) δ 8.51 (s, 1H, ArH), 8.11 (s, 1H, ArH), 7.91(dd, 1H, ArH), 7.73 (d, 1H, ArH), 7.30 (dd, 1H, ArH), 7.16 (d, 1H, ArH),6.87 (d, 1H, ArH), 5.60 (s, 2H, ArCH₂), 3.95 (s, 3H, CH₃), 3.88 (s, 3H,CH₃).

LC-MS: m/z 331 M+H⁺.

Step 2 2-(5-Chloro-2-hydroxy-benzyl)-2H-indazole-5-carboxylic acidmethyl ester 43

The title compound was prepared following the method in Example 3, Step2.

¹H-NMR (CDCl₃, 300 MHz) δ 10.53 (s, 1H, ArOH), 8.52 (s, 1H, ArH), 8.21(s, 1H, ArH), 7.99 (dd, 1H, ArH), 7.70 (d, 1H, ArH), 7.33-7.21 (m, 2H,ArH), 6.99 (d, 1H, ArH), 5.50 (s, 2H, ArCH₂), 3.96 (s, 3H, CH₃.

LC-MS: m/z 317 M+H⁺.

Step 3 2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acidmethyl ester, 44

The title compound was prepared following the method in Example 3, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.49 (s, 1H, ArH), 8.09 (s, 1H, ArH), 7.91(dd, 1H, ArH), 7.73 (d, 1H, ArH), 7.27 (dd, 1H, ArH), 7.14 (d, 1H, ArH),6.83 (d, 1H, ArH), 5.62 (s, 2H, ArCH₂), 3.94 (s, 3H, CH₃), 3.76 (d, 2H,CH₂). 2.10 (m, 1H, CH), 1.00 (d, 6H, CH₃).

LC-MS: m/z 373 M+H⁺.

Step 4 2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid, 45

The title compound was prepared following the method in Example 1, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.57 (s, 1H, ArH), 8.12 (s, 1H, ArH), 7.95(dd, 1H, ArH), 7.76 (d, 1H, ArH), 7.28 (dd, 1H, ArH), 7.16 (d, 1H, ArH),6.85 (d, 1H, ArH), 5.63 (s, 2H, ArCH₂), 3.77 (d, 2H, CH₂). 2.11 (m, 1H,CH), 1.01 (d, 6H, CH₃).

LC-MS: m/z 359 M+H⁺.

Example 17 2-(5-Bromo-2-Isobutoxy-Benzyl)-2H-Indazole-5-Carboxylic Acid,49

Step 1 2-(5-Bromo-2-methoxy-benzyl)-2H-indazole-5-carboxylic acid methylester 46

The title compound was prepared following the method in Example 3, Step1.

¹H-NMR (CDCl₃, 300 MHz) δ 8.50 (s, 1H, ArH), 8.11 (s, 1H, ArH), 7.92(dd, 1H, ArH), 7.73 (d, 1H, ArH), 7.45 (dd, 1H, ArH), 7.30 (d, 1H, ArH),6.82 (d, 1H, ArH), 5.60 (s, 2H, ArCH₂), 3.95 (s, 3H, CH₃), 3.87 (s, 3H,CH₃).

LC-MS: m/z 376 M+H⁺.

Step 2 2-(5-Bromo-2-hydroxy-benzyl)-2H-indazole-5-carboxylic acid methylester 47

The title compound was prepared following the method in Example 3, Step2.

¹H-NMR (CDCl₃, 300 MHz) 10.59 (broad s, 1H, ArOH), 8.52 (s, 1H, ArH),8.21 (s, 1H, ArH), 7.99 (dd, 1H, ArH), 7.70 (d, 1H, ArH), 7.45-7.36 (m,2H, ArH), 6.94 (d, 1H, ArH), 5.49 (s, 2H, ArCH₂), 3.96 (s, 3H, CH₃.

LC-MS: m/z 362 M+H⁺.

Step 3 2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acidmethyl ester, 48

The title compound was prepared following the method in Example 3, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.50 (s, 1H, ArH), 8.09 (s, 1H, ArH), 7.92(dd, 1H, ArH), 7.73 (d, 1H, ArH), 7.43 (dd, 1H, ArH), 7.29 (d, 1H, ArH),6.80 (d, 1H, ArH), 5.62 (s, 2H, ArCH₂), 3.95 (s, 3H, CH₃), 3.76 (d, 2H,CH₂). 2.10 (m, 1H, CH), 1.00 (d, 6H, CH₃).

LC-MS: m/z 417M+H⁺.

Step 4 2-(5-Bromo-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid, 49

The title compound was prepared following the method in Example 1, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.60 (s, 1H, ArH), 8.12 (s, 1H, ArH), 7.96(dd, 1H, ArH), 7.77 (d, 1H, ArH), 7.43 (dd, 1H, ArH), 7.32 (d, 1H, ArH),6.80 (d, 1H, ArH), 5.64 (s, 2H, ArCH₂), 3.77 (d, 2H, CH₂). 2.11 (m, 1H,CH), 1.01 (d, 6H, CH₃).

Example 181-(2-(Trifluoromethyl)-5-Isobutoxy-Benzyl)-1H-Indazole-5-CarboxylicAcid, 53

Step 1 1-(5-(Trifluoromethyl)-2-methoxy-benzyl)-1H-indazole-5-carboxylicacid methyl ester, 50

The title compound was prepared following the method in Example 3,Step 1. But using (5-(trifluoromethyl)-2-methoxy-phenyl)-methanol,instead of (5-chloro-2-methoxy-phenyl)-methanol.

¹H-NMR (CDCl₃, 300 MHz) δ 8.54 (s, 1H, ArH), 8.16 (s, 1H, ArH), 8.07(dd, 1H, ArH), 7.53 (d, 1H, ArH), 7.45 (dd, 1H, ArH), 7.23 (m, 1H, ArH),6.94 (d, 1H, ArH), 5.62 (s, 2H, ArCH₂), 3.91 (s, 3H, CH₃), 3.90 (s, 3H,CH₃).

Step 2 1-(2-(trifluoromethyl)-5-hydroxy-benzyl)-1H-indazole-5-carboxylicacid methyl ester, 51

The title compound was prepared following the method in Example 3, Step2

¹H-NMR (CDCl₃, 300 MHz) δ 8.54 (s, 1H, ArH), 8.16 (s, 1H, ArH), 8.07(dd, 1H, ArH), 7.53 (d, 1H, ArH), 7.45 (dd, 1H, ArH), 7.23 (m, 1H, ArH),6.94 (d, 1H, ArH), 5.54 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃).

LC-MS: m/z 351 M+H⁺.

Step 31-(2-(trifluromethyl)-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acidmethyl ester, 52

The title compound was prepared following the method in Example 3, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.17 (s, 1H, ArH), 8.05(dd, 1H, ArH), 7.52 (dd, 1H, ArH), 7.43 (d, 1H, ArH), 7.17 (m, 1H, ArH),6.95 (d, 1H, ArH), 5.65 (s, 2H, ArCH₂), 3.96 (s, 3H, CH₃), 3.82 (d, 2H,—OCH₂CH(CH₃)₂), 2.11 (m, 1H, —OCH₂CH(CH₃)₂), 1.02 (d, 3H,—OCH₂CH(CH₃)₂), 0.87 (d, 3H, —OCH₂CH(CH₃)₂).

Step 41-(2-(trifluoromethyl)-5-isobutoxy-benzyl)-1H-indazole-5-carboxylicacid, 53

The title compound was prepared following the method in Example 1, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.66 (s, 1H, ArH), 8.22 (s, 1H, ArH), 8.12(dd, 1H, ArH), 7.53 (dd, 1H, ArH), 7.47 (d, 1H, ArH), 7.22 (m, 1H, ArH),6.95 (d, 1H, ArH), 5.68 (s, 2H, ArCH₂), 3.83 (d, 2H, —OCH₂CH(CH₃)₂),2.14 (m, 1H, —OCH₂CH(CH₃)₂), 1.02 (d, 6H, —OCH₂CH(CH₃)₂).

LC-MS: m/z 393 M+H⁺.

Example 191-(5-Bromo-2-Cyclopropyl-2-Methylmethoxy-Benzyl)-1H-Indazole-5-CarboxylicAcid, 55

Step 11-(5-Bromo-2-cyclopropyl-2-methylmethoxy-benzyl)-1H-indazole-5-carboxylicacid methyl ester, 54

The title compound was prepared following the method in Example 3, Step3.

H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.15 (s, 1H, ArH), 8.05 (dd,1H, ArH), 7.55 (d, 1H, ArH), 7.34 (dd, 1H, ArH), 7.10 (d, 1H, ArH), 6.70(d, 1H, ArH), 5.65 (s, 2H, ArCH₂), 3.97 (s, 3H, CH₃), 3.75 (s, 2H, CH₂),1.20 (s, 3H, CH₃), 0.55 (m, 2H, CH₂), 0.45 (m, 2H, CH₂).

LC-MS: m/z 430 M+H⁺.

Step 21-(5-Bromo-2-cyclopropyl-2-methylmethoxy-benzyl)-1H-indazole-5-carboxylicacid, 55

The title compound was prepared following the method in Example 1, Step3.

H-NMR (CDCl₃, 300 MHz) δ 8.65 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.10 (dd,1H, ArH), 7.60 (d, 1H, ArH), 7.34 (dd, 1H, ArH), 7.10 (d, 1H, ArH), 6.70(d, 1H, ArH), 5.65 (s, 2H, ArCH₂), 3.75 (s, 2H, CH₂), 1.20 (s, 3H, CH₃),0.55 (m, 2H, CH₂), 0.45 (m, 2H, CH₂).

LC-MS: m/z 416 M+H⁺.

Example 201-(2-Isobutoxy-5-Trifluoromethoxy-Benzyl)-1H-Indazole-5-Carboxylic Acid,60

Step 1 2-Isobutoxy-5-trifluoromethoxy-benzaldehyde, 56

A solution of 2-Hydroxy-5-trifluoromethoxy-benzaldehyde (1.0 g, 4.9mmole) in DMF (10 ml) was treated with potassium carbonate (1.5 g, 10.9mmole) and tetrabutylammonium iodide (0.01 g) and1-chloro-2-methylpropane (1.05 ml, 10 mmole). The mixture was stirred at110° C. under a nitrogen atmosphere for 18 h. The mixture was thenevaporated to dryness and the residue partitioned between ethyl acetate(50 ml) and water (50 ml). The organic extract was separated then washedwith saturated brine then dried over sodium sulphate, filtered andevaporated to dryness. The residue was chromatographed on silica geleluting with a gradient of 5-15% ethyl acetate/isohexane. This gave thetitle compound as a pale yellow oil (1.02 g, 80%).

H-NMR (CDCl₃, 300 MHz) δ10.49 (s, 1H, CHO), 7.71 (d, 1H, ArH), 7.38 (dd,1H, ArH), 6.95 (d, 1H, ArH), 3.89 (d, 2H, CH₂), 2.15-2.28 (m, 1H, CH),1.05 (d, 6H, 2×CH₃).

Step 2 (2-Isobutoxy-5-trifluoromethoxy-phenyl)-methanol, 57

A solution of 2-Isobutoxy-5-trifluoromethoxy-benzaldehyde (1.02 g, 3.9mmole) in methanol (20 ml) was treated with sodium borohydride (0.22 g,5.8 mmole) then stirred at ambient temperature under a nitrogenatmosphere for 2 h. The mixture was evaporated to dryness and theresidue partitioned between water (50 ml) and dichloromethane (2×50 ml).The combined organic extracts were dried over sodium sulphate, filteredand evaporated to dryness. The residue was chromatographed on silica geleluting with a gradient of 10-20% ethyl acetate/isohexane. This gave thetitle compound as a colorless oil (1.0 g, 97%).

H-NMR (CDCl₃, 300 MHz) δ7.22 s, 1H, ArH), 7.09 (dd, 1H, ArH), 6.41 (d,1H, ArH), 4.71 (d, 2H, CH₂), 3.81 (d, 2H, CH₂), 2.23 (t, 1H, OH),2.07-2.19 (m, 1H, CH), 1.07 (d, 6H, 2×CH₃).

Step 3

Methanesulfonic acid 2-isobutoxy-5-trifluoromethoxy-benzyl ester, 58

A solution of (2-Isobutoxy-5-trifluoromethoxy-phenyl)-methanol (1.0 g,3.8 mmole) in dichloromethane (50 ml) was treated withdiisopropylethylamine (0.73 ml, 4.2 mmole) and methanesulphonicanhydride (0.73 g, 4.2 mmole) then stirred at ambient temperature undera nitrogen atmosphere for 1.5 h. The mixture was then washed with water(50 ml) and saturated brine (50 ml). The organic layer was dried oversodium sulphate, filtered and evaporated to dryness to give the titlecompound as a colorless oil (1.2 g, 92%).

H-NMR (CDCl₃, 300 MHz) δ 7.27 (s, 1H, ArH), 7.19 (dd, 1H, ArH), 6.92 (d,1H, ArH), 5.29 (s, 2H, CH₂), 3.79 (d, 2H, CH₂), 2.99 (s, 3H, CH₃),2.07-2.19 (m, 1H, CH), 1.05 (d, 6H, 2×CH₃).

Step 41-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylic acidmethyl ester, 59

A solution of 1H-Indazole-5-carboxylic acid methyl ester (0.154 g, 0.88mmole) in DMF (5 ml) was treated with sodium hydride (60% dispersion inoil) (0.042 g, 1 mmole) then stirred at ambient temperature under anitrogen atmosphere for 1 h. A solution of methanesulfonic acid2-isobutoxy-5-trifluoromethoxy-benzyl ester (0.3 g, 0.88 mmole) in DMF(5 ml) was then added and the mixture stirred at ambient temperature for18 h. The mixture was evaporated to dryness and the residue partitionedbetween water (20 ml) and dichloromethane (2×20 ml). The combinedorganics were dried over sodium sulphate, filtered and evaporated todryness. The residue was chromatographed using silica gel eluting with agradient of 5-20% ethyl acetate/isohexane to give in the early fractionsthe title compound (0.217 g, 59%) as a white solid. The corresponding2-yl-indazole isomer eluted in the later column fractions.

H-NMR (CDCl₃, 300 MHz) δ8.55 (s, 1H, ArH), 8.15 (s, 1H, ArH), 8.01 (dd,1H, ArH), 7.41 (d, 1H, ArH), 7.11 (dd, 1H, ArH), 6.88 (d, 1H, ArH), 6.71(s, 1H, ArH), 5.61 (s, 2H, CH₂), 3.99 (s, 3H, CH₃), 3.78 (d, 2H, CH₂),2.05-2.19 (m, 1H, CH), 1.04 (d, 6H, 2×CH₃).

Step 51-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylic acid,60

A solution of1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylicacidmethylester (0.217 g, 0.51 mmole) in 1,4-dioxane (20 ml) was treated with 2Msodium hydroxide (20 ml) and the mixture stirred at 60° C. for 18 h. Themixture was evaporated to dryness and the residue dissolved in water (20ml) then acidified to pH1 with 2M hydrochloric acid. The resultingprecipitate was extracted into ethyl acetate (2×50 ml). The combinedorganics were dried over sodium sulphate, filtered and evaporated todryness. The residue was chromatographed on silica gel eluting with agradient of 0.75-2% methanol/dichloromethane to give the title compoundas a white solid (0.154 g, 73%).

H-NMR (CDCl₃, 300 MHz) δ8.68 (s, 1H, ArH), 8.21 (s, 1H, ArH), 8.11 (dd,1H, ArH), 7.48 (d, 1H, ArH), 7.11 (dd, 1H, ArH), 6.88 (d, 1H, ArH), 6.72(s, 1H, ArH), 5.67 (s, 2H, CH₂), 3.79 (d, 2H, CH₂), 2.05-2.19 (m, 1H,CH), 1.03 (d, 6H, 2×CH₃).

LC-MS m/z 409 M+H⁺.

Example 211-(5-Bromo-2-Isobutoxy-Benzyl)-3-Methyl-1H-Indazole-5-Carboxylic Acid,65

Step 1 5-Bromo-2-isobutoxy-benzaldehyde, 61

The title compound was prepared following the method in Example 20, Step1.

H-NMR (CDCl₃, 300 MHz) δ10.52 (s, 1H, CHO), 7.95 (d, 1H, ArH), 7.61 (dd,1H, ArH), 6.93 (s, 1H, ArH), 3.85 (d, 2H, CH₂), 2.12-2.24 (m, 1H, CH),1.09 (d, 6H, 2×CH₃).

Step 2 (5-Bromo-2-isobutoxy-phenyl)-methanol, 62

The title compound was prepared following the method in Example 20, Step2.

H-NMR (CDCl₃, 300 MHz) δ 7.45 (d, 1H, ArH), 7.36 (dd, 1H, ArH), 6.77 (d,1H, ArH), 4.69 (d, 2H, CH₂), 3.78 (d, 2H, CH₂), 2.27 (t, 1H, OH),2.07-2.21 (m, 1H, CH), 1.07 (d, 6H, 2×CH₃).

Step 3 Methanesulfonic acid 5-bromo-2-isobutoxy-benzyl ester, 63

The title compound was prepared following the method in Example 20, Step3.

H-NMR (CDCl₃, 300 MHz) δ7.49 (d, 1H, ArH), 7.45 (dd, 1H, ArH), 6.79 (d,1H, ArH), 5.27 (s, 2H, CH₂), 3.77 (d, 2H, CH₂), 3.01 (s, 3H, CH₃),2.07-2.20 (m, 1H, CH), 1.06 (d, 6H, 2×CH₃).

Step 4 1-(5-Bromo-2-isobutoxy-benzyl)-3-methyl-1H-indazole-5-carboxylicacid methyl ester, 64

To a mixture of methanesulfonic acid 5-bromo-2-isobutoxy-benzyl ester(0.044 g, 0.1 mmole) and 3-Methyl-1H-indazole-5-carboxylic acid methylester (0.02 g, 0.1 mmole) in DMF was added cesium carbonate (0.051 g,0.15 mmole) and the mixture stirred at ambient temperature for 18 hunder a nitrogen atmosphere. The mixture was evaporated to dryness andthe residue partitioned between water (10 ml) and dichloromethane (2×20ml). The combined organics were dried over sodium sulphate, filtered andevaporated to dryness. The residue was chromatographed on silica geleluting with a gradient of 5-20% ethyl acetate/isohexane to give thetitle compound (0.04 g) as a colorless oil.

H-NMR (CDCl₃, 300 MHz) δ8.48 (s, 1H, ArH), 8.02 (d, 1H, ArH), 7.30-7.37(m, 2H, 2×ArH), 6.96 (d, 1H, ArH), 6.76 (d, 1H, ArH), 5.52 (s, 2H, CH₂),3.99 (s, 3H, CH₃), 3.77 (d, 2H, CH₂), 2.65 (s, 3H, CH₃), 2.05-2.19 (m,1H, CH), 1.04 (d, 6H, 2×CH₃).

Step 5 1-(5-Bromo-2-isobutoxy-benzyl)-3-methyl-1H-indazole-5-carboxylicacid, 65

The title compound was prepared following the method in Example 20, Step5.

1H-NMR (CDCl₃, 300 MHz) δ8.59 (s, 1H, ArH), 8.09 (d, 1H, ArH), 7.33-7.41(m, 2H, 2×ArH), 6.98 (d, 1H, ArH), 6.77 (d, 1H, ArH), 5.59 (s, 2H, CH₂),3.78 (d, 2H, CH₂), 2.68 (s, 3H, CH₃), 2.07-2.20 (m, 1H, CH), 1.06 (d,6H, 2×CH₃).

LC-MS m/z 417 and 419 M+H⁺.

Example 221-(2-Isobutoxy-5-Trifluoromethoxy-Benzyl)-3-Methyl-1H-Indazole-5-CarboxylicAcid, 66

The title compound was prepared following the methods described onExample 21 but using compound 58 as the starting material.

1H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.08 (dd, 1H, ArH), 7.35(d, 1H, ArH), 7.11 (dd, 1H, ArH), 6.95 (d, 1H, ArH), 6.71 (d, 1H, ArH),5.58 (s, 2H, CH₂), 3.79 (d, 2H, CH₂), 2.66 (s, 3H, CH₃), 2.07-2.21 (m,1H, CH), 1.05 (d, 6H, 2×CH₃).

Example 231-[5-Chloro-2-(2-Ethyl-Butoxy)-Benzyl]-3-Methyl-1H-Indazole-5-CarboxylicAcid, 67

The title compound was prepared following the methods described onExample 21 but using 2-Hydroxy-5-chloro-benzaldehyde as startingmaterial.

1H-NMR (CDCl₃, 300 MHz) δ 8.58 (s, 1H, ArH), 8.07 (dd, 1H, ArH), 7.34(d, 1H, ArH), 7.18 (dd, 1H, ArH), 6.85 (d, 1H, ArH), 6.76 (d, 1H, ArH),5.56 (s, 2H, CH₂), 3.91 (d, 2H, CH₂), 2.66 (s, 3H, CH₃), 1.63-1.78 (m,1H, CH), 1.41-1.53 (m, 4H, 2×CH₂), 0.94 (t, 6H, 2×CH₃).

Example 241-(5-Chloro-2-Isobutoxy-Benzyl)-3-Methyl-1H-Indazole-5-Carboxylic Acid,68

The title compound was prepared following the methods described onExample 21 but using 2-Hydroxy-5-chloro-benzaldehyde as startingmaterial.

1H-NMR (CDCl₃, 300 MHz) δ 8.59 (s, 1H, ArH), 8.09 (dd, 1H, ArH), 7.37(d, 1H, ArH), 7.18 (dd, 1H, ArH), 6.79 (s, 1H, ArH), 6.77 (d, 1H, ArH),5.55 (s, 2H, CH₂), 3.78 (d, 2H, CH₂), 2.67 (s, 3H, CH₃), 2.04-2.29 (m,1H, CH), 1.03 (d, 6H, 2×CH₃).

Example 251-(2-Isobutoxy-5-Trifluoromethyl-Benzyl)-3-Methyl-1H-Indazole-5-CarboxylicAcid, 69

The title compound was prepared following the methods described onExample 21 but using 2-Hydroxy-5-(trifluoromethyl)-benzaldehyde asstarting material.

1H-NMR (CDCl₃, 300 MHz) δ 8.59 (s, 1H, ArH), 8.11 (dd, 1H, ArH), 7.55(dd, 1H, ArH), 7.39 (d, 1H, ArH), 7.19 (d, 1H, ArH), 6.97 (d, 1H, ArH),5.61 (s, 2H, CH₂), 3.85 (d, 2H, CH₂), 2.69 (s, 3H, CH₃), 2.05-2.21 (m,1H, CH), 1.03 (d, 6H, 2×CH₃).

Example 261-[2-(2-Ethyl-Butoxy)-5-Trifluoromethyl-Benzyl]-3-Methyl-1H-Indazole-5-CarboxylicAcid, 70

The title compound was prepared following the methods described onExample 21 but using 2-Hydroxy-5-(trifluoromethyl)-benzaldehyde asstarting material.

1H-NMR (CDCl₃, 300 MHz) δ 8.59 (s, 1H, ArH), 8.09 (dd, 1H, ArH), 7.56(dd, 1H, ArH), 7.38 (d, 1H, ArH), 7.16 (d, 1H, ArH), 6.99 (d, 1H, ArH),5.61 (s, 2H, CH₂), 3.97 (d, 2H, CH₂), 2.66 (s, 3H, CH₃), 1.68-1.79 (m,1H, CH), 1.45-1.54 (m, 4H, 2×CH₂), 0.97 (t, 6H, 2×CH₃).

Example 271-[5-Bromo-2-(2-Ethyl-Butoxy)-Benzyl]-3-Methyl-1H-Indazole-5-CarboxylicAcid, 71

The title compound was prepared following the methods described onExample 21 but using 2-Hydroxy-5-bromo-benzaldehyde as startingmaterial.

1H-NMR (CDCl₃, 300 MHz) δ 8.59 (s, 1H, ArH), 8.09 (dd, 1H, ArH),7.31-7.39 (m, 2H, 2×ArH), 6.96 (d, 1H, ArH), 6.79 (d, 1H, ArH), 5.55 (s,2H, CH₂), 3.92 (d, 2H, CH₂), 2.69 (s, 3H, CH₃), 1.66-1.76 (m, 1H, CH),1.42-1.54 (m, 4H, 2×CH₂), 0.95 (t, 6H, 2×CH₃).

Example 281-[5-Bromo-2-(1-Methyl-Cyclopropylmethoxy)-Benzyl]-3-Methyl-1H-Indazole-5-CarboxylicAcid, 72

The title compound was prepared following the methods described onExample 21 but using 2-Hydroxy-5-bromo-benzaldehyde as startingmaterial.

¹H-NMR (CDCl₃, 300 MHz) δ 8.59 (s, 1H, ArH), 8.12 (dd, 1H, ArH), 7.48(d, 1H, ArH), 7.34 (dd, 1H, ArH), 7.09 (d, 1H, ArH), 6.71 (d, 1H, ArH),5.58 (s, 2H, CH₂), 3.77 (s, 2H, CH₂), 2.67 (s, 3H, CH₃), 1.23 (s, 3H,CH₃), 0.42-0.59 (m, 4H, 2×CH₂).

Example 291-[5-Chloro-2-(1-Methyl-Cyclopropylmethoxy)-Benzyl]-3-Methyl-1H-Indazole-5-CarboxylicAcid, 73

The title compound was prepared following the methods described onExample 21 but using 2-Hydroxy-5-chloro-benzaldehyde as startingmaterial.

¹H-NMR (CDCl₃, 300 MHz) δ 8.58 (s, 1H, ArH), 8.08 (d, 1H, ArH), 7.47 (d,1H, ArH), 7.19 (dd, 1H, ArH), 6.95 (d, 1H, ArH), 6.74 (d, 1H, ArH), 5.58(s, 2H, CH₂), 3.78 (s, 2H, CH₂), 2.69 (s, 3H, CH₃), 1.22 (s, 3H, CH₃),0.43-0.57 (m, 4H, 2×CH₂).

Example 301-(5-Bromo-2-Isobutoxy-Benzyl)-1H-Pyrrolo[2,3-b]Pyridine-5-CarboxylicAcid, 77

Step 1 5-bromo-1H-pyrrolo[2,3-b]pyridine, 74

Following the preparation procedure described in WO2006015124, which ishereby incorporated by reference in its entirety,5-bromo-1H-pyrrolo[2,3-b]pyridine was isolated after columnchromatography on silica as a light brown solid (30% over 3 steps).LC-MS: m/z 198, 200 M+H⁺.

Step 2 1h-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester, 75

To a mixture of 5-Bromo-1H-pyrrolo[2,3-b]pyridine 0.6 g (3 mmol),molybdenum hexacarbonate 0.4 g (1.5 mmol), Herrmann's catalyst 0.28 g,4,4-bis(diphenylphosphino)-9,9-dimethylxanthane and triethylamine 0.85ml (6 mmol) in a 20 ml microwave reactor THF (10 ml) and methanol (2 ml)was added. The resulting suspension was heated at 150° C. on microwavefor 10 minutes. The mixture was poured into sat NH₄Cl (aq.) andextracted twice with EtOAC. The organic layers were combined, washedwith sat NH₄Cl (aq.), dried (MgSO₄) and the volatiles were removed invacuo. The crude product was purified on silica to yield1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester 2 0.16 g as abrown solid (30%).

¹H-NMR (CDCl₃, 300 MHz) δ 9.28 (d, 1H, ArH), 8.86 (d, 1H, ArH), 8.25 (s,1H, ArH), 4.02 (s, 3H, CH₃)

LC-MS: m/z 178 M+H⁺.

Step 31-(5-Bromo-2-isobutoxy-benzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid methyl ester, 76

The title compound was prepared following the method in Example 21, Step4.

¹H-NMR (CDCl₃, 300 MHz) δ 9.22 (d, 1H, ArH), 8.79 (d, 1H, ArH), 8.19 (s,1H, ArH), 7.34 (dd, 1H, ArH), 6.98 (d, 1H, ArH), 6.74 (d, 1H, ArH), 5.77(s, 2H, ArCH₂), 4.01 (s, 3H, CH₃), 3.72 (d, 2H, CH₂). 2.01 (m, 1H, CH),0.97 (d, 6H, CH₃).

LC-MS: m/z 374, 376 M+H⁺

Step 41-(5-bromo-2-isobutoxy-benzyl)-1h-pyrazolo[3,4-b]pyridine-5-carboxylicacid, 77

The title compound was prepared following the method in Example 20, Step5.

¹H-NMR (CDCl₃, 300 MHz) δ 9.28 (s, 1H, ArH), 8.85 (s, 1H, ArH), 8.18 (s,1H, ArH), 7.33 (d, 1H, ArH), 6.99 (s, 1H, ArH), 6.74 (d, 1H, ArH), 5.76(s, 2H, ArCH₂), 3.71 (d, 2H, CH₂). 2.01 (m, 1H, CH), 0.96 (d, 6H, CH₃).

LC-MS: m/z 405 M+H⁺

Example 311-[5-Bromo-2-(2-Ethyl-Butoxy)-Benzyl]-1H-Pyrrolo[2,3-b]Pyridine-5-CarboxylicAcid, 82

Step 1 5-Bromo-2-(2-ethyl-butoxy)-benzaldehyde 78

A solution of 5-bromosalicaldehyde (2.0 g, 10 mmole) in DMF (50 ml) wastreated with potassium carbonate (3 g, 22 mmole) and tetrabutylammoniumiodide (0.22 g) and 3-chloromethylpentane (1.65 ml, 12.2 mmole). Themixture was stirred at 110° C. under a nitrogen atmosphere for 18 h. Themixture was then evaporated to dryness and the residue partitionedbetween ethyl acetate (50 ml) and water (50 ml). The organic extract wasseparated then washed with saturated brine then dried over sodiumsulphate, filtered and evaporated to dryness. The residue waschromatographed on silica gel eluting with a gradient of 5-15% ethylacetate/isohexane. This gave the title compound as a pale yellow oil(2.24 g, 78%).

¹H-NMR (CDCl₃, 300 MHz) δ10.49 (s, 1H, CHO), 7.95 (d, 1H, ArH), 7.63(dd, 1H, ArH), 6.90 (d, 1H, ArH), 4.00 (d, 2H, CH₂), 1.80 (m, 1H, CH),1.55 (s, 4H, 2×CH₂—CH₃), 1.00 (q, 6H, 2×CH₂—CH₃)

Step 2 [5-Bromo-2-(2-ethyl-butoxy)-phenyl]methanol, 79

The title compound was prepared following the method in Example 20, Step2.

¹H-NMR (CDCl₃, 300 MHz) δ7.45 (d, 1H, ArH), 7.37 (dd, 1H, ArH), 6.80 (d,1H, ArH), 4.70 (d, 2H, —CH₂OH), 3.90 (d, 2H, CH₂), 1.80 (m, 1H, CH),1.55 (s, 4H, 2×CH₂—CH₃), 1.00 (q, 6H, 2×CH₂—CH₃).

Step 3 Methanesulfonic acid 5-bromo-2-(2-ethyl-butoxy)-benzyl ester, 80

The title compound was prepared following the method in Example 20, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ7.55 (d, 1H, ArH), 7.45 (dd, 1H, ArH), 6.80 (d,1H, ArH), 5.75 (d, 2H, —CH₂OSO₂CH₃), 3.90 (d, 2H, CH₂), 3.00 (s, 3H,CH₂OSO₂CH₃), 1.80 (m, 1H, CH), 1.55 (s, 4H, 2×CH₂—CH₃), 1.00 (q, 6H,2×CH₂—CH₃)

Step 41-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid methyl ester, 81

The title compound was prepared following the method in Example 21, Step4.

¹H-NMR (CDCl₃, 300 MHz) δ 9.21 (d, 1H, ArH), 8.80 (d, 1H, ArH), 8.19 (s,1H, ArH), 7.34 (dd, 1H, ArH), 6.95 (d, 1H, ArH), 6.77 (d, 1H, ArH), 5.76(s, 2H, ArCH₂), 4.01 (s, 3H, CH₃), 3.85 (d, 2H, CH₂). 1.60 (m, 1H, CH),1.39 (m, 4H, CH₂), 0.88 (m, 6H, CH₃).

LC-MS: m/z 446, 448 M+H⁺

Step 51-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazolo[3,4-b]pyridine-5-carboxylicacid, 82

The title compound was prepared following the method in Example 20, Step5.

¹H-NMR (CDCl₃, 300 MHz) δ 9.30 (d, 1H, ArH), 8.87 (d, 1H, ArH), 8.24 (s,1H, ArH), 7.36 (dd, 1H, ArH), 7.00 (d, 1H, ArH), 6.78 (d, 1H, ArH), 5.78(s, 2H, ArCH₂), 3.86 (d, 2H, CH₂). 1.60 (m, 1H, CH), 1.39 (m, 4H, CH₂),0.89 (m, 6H, CH₃).

LC-MS: m/z 432,434 M+H⁺.

Example 321-[2-(4-Chloro-Benzyloxy)-5-Trifluoromethyl-Benzyl]-1H-Indazole-5-CarboxylicAcid, 83

The title compound was prepared starting from compound 51 and followingthe methods in Example 8, Step 1 and Example 1, step 3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.65 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.00 (d,1H, ArH), 7.55 (d, 1H, ArH), 7.40-7.20 (m, 6H, ArH), 7.00 (d, 1H, ArH),5.65 (s, 2H, ArCH₂O), 5.05 (s, 2H, ArCH₂Het).

LC-MS: m/z 461 M+H⁺.

Example 331-(2-Cyclopentylmethoxy-5-Trifluoromethyl-Benzyl)-1H-Indazole-5-CarboxylicAcid, 84

The title compound was prepared starting from compound 51 and followingthe methods in Example 3, Step 3 and Example 1, step 3.

¹H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.10 (d,1H, ArH), 7.65 (d, 1H, ArH), 7.53 (d, 1H, ArH), 7.42 (s, 1H, ArH), 6.87(d, 1H, ArH), 5.65 (s, 2H, ArCH₂Het), 4.85 (d, 2H, —CH₂O—), 1.7 (m, 1H,CH), 1.4-0.6 (m, 8H, —CH₂—).

LC-MS: m/z 391 M+H⁺.

Example 341-(5-Chloro-2-Cyclopropylmethoxy-Benzyl)-1H-Indazole-4-Carboxylic Acid,85

The title compound was prepared following the same method as Example 7.

¹H-NMR (CDCl₃, 300 MHz) δ 8.62 (s, 1H, ArH), 8.05 (d, 1H, ArH), 7.82 (d,1H, ArH), 7.45 (m, 1H, ArH), 7.20 (m, 1H, ArH), 7.00 (s, 1H, ArH), 6.75(m, 1H, ArH), 5.65 (s, 2H, ArCH₂Het), 3.80 (d, 2H, —CH₂O—), 1.55 (m, 1H,CH), 0.7 (m, 2H, —CH₂—), 0.4 (m, 2H, —CH₂—). LC-MS: m/z 357 M+H⁺.

Example 352-(5-Chloro-2-Cyclopropylmethoxy-Benzyl)-2H-Indazole-4-Carboxylic Acid,86

The title compound was prepared following the same method as Example 7.

¹H-NMR (DMSO, 300 MHz) δ 8.70 (s, 1H, ArH), 8.05 (d, 1H, ArH), 7.85 (d,1H, ArH), 7.75 (d, 1H, ArH), 7.32 (m, 2H, ArH), 7.20 (s, 1H, ArH), 7.00(d, 1H, ArH), 5.65 (s, 2H, ArCH₂Het), 3.85 (d, 2H, —CH₂O—), 1.70 (m, 1H,CH), 0.55 (m, 2H, —CH₂—), 0.3 (m, 2H, —CH₂—). LC-MS: m/z 357 M+H⁺.

Example 36 1-(5-Chloro-2-Isobutoxy-Benzyl)-1H-Indazole-4-CarboxylicAcid, 87

The title compound was prepared following the same method as Example 7.

¹H-NMR (CDCl₃, 300 MHz) δ 8.62 (s, 1H, ArH), 8.05 (d, 1H, ArH), 7.70 (d,1H, ArH), 7.45 (m, 1H, ArH), 7.15 (m, 1H, ArH), 6.80 (m, 2H, ArH), 5.65(s, 2H, ArCH₂Het), 3.75 (d, 2H, —CH₂O—), 2.10 (m, 1H, CH), 1.05 (d, 6H,—CH₃).

LC-MS: m/z 359 M+H⁺.

Example 37 2-(5-Chloro-2-Isobutoxy-Benzyl)-2H-Indazole-4-CarboxylicAcid, 88

The title compound was prepared following the same method as Example 7.

¹H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.15 (m, 2H, ArH), 7.40 (t,1H, ArH), 7.25 (m, 1H, ArH), 7.10 (s, 1H, ArH), 6.80 (d, 1H, ArH), 5.65(s, 2H, ArCH₂Het), 3.75 (d, 2H, —CH₂O—), 2.15 (m, 1H, CH), 1.05 (d, 6H,—CH₃).

LC-MS: m/z 359 M+H⁺.

Example 381-[5-Chloro-2-(2-Ethyl-Butoxy)-Benzyl]-1H-Indazole-4-Carboxylic Acid, 89

The title compound was prepared following the same method as Example 7.

¹H-NMR (CDCl₃, 300 MHz) δ 8.65 (s, 1H, ArH), 8.05 (d, 1H, ArH), 7.65 (d,1H, ArH), 7.52 (t, 1H, ArH), 7.18 (m, 1H, ArH), 6.85 (d, 1H, ArH), 6.75(m, 1H, ArH), 5.65 (s, 2H, ArCH₂Het), 3.90 (d, 2H, —CH₂O—), 1.50 (m, 1H,CH), 1.45 (t, 4H, —CH₂CH₃), 0.95 (t, 6H, —CH₂CH₃). LC-MS: m/z 387 M+H⁺.

Example 392-[5-Chloro-2-(2-Ethyl-Butoxy)-Benzyl]-2H-Indazole-4-Carboxylic Acid, 90

The title compound was prepared following the same method as Example 7.

¹H-NMR (CDCl₃, 300 MHz) δ 8.50 (s, 1H, ArH), 8.02 (m, 2H, ArH), 7.40 (t,1H, ArH), 7.25 (m, 1H, ArH), 7.15 (s, 1H, ArH), 6.82 (d, 1H, ArH), 5.65(s, 2H, ArCH₂Het), 3.90 (d, 2H, —CH₂O—), 1.70 (m, 1H, CH), 1.45 (t, 4H,—CH₂CH₃), 0.85 (t, 6H, —CH₂CH₃).

LC-MS: m/z 387 M+H⁺.

Example 401-[5-Chloro-2-(4-Chloro-Benzyloxy)-Benzyl]-1H-Indazole-4-CarboxylicAcid, 91

The title compound was prepared following the same method as Example 7.

¹H-NMR (CDCl₃, 300 MHz) δ 8.52 (s, 1H, ArH), 8.02 (d, 1H, ArH), 7.55 (d,1H, ArH), 7.40-7.20 (m, 6H, ArH), 7.00 (s, 1H, ArH), 6.85 (d, 1H, ArH),5.65 (s, 2H, ArCH₂Het), 5.05 (s, 2H, ArCH₂O—). LC-MS: m/z 427 M+H⁺.

Example 412-[5-Chloro-2-(4-Chloro-Benzyloxy)-Benzyl]-2H-Indazole-4-CarboxylicAcid, 92

The title compound was prepared following the same method as Example 7.

¹H-NMR (DMSO, 300 MHz) δ 13.00 (s, 1H, COOH), 8.65 (s, 1H, ArH), 7.90(m, 1H, ArH), 7.80 (d, 1H, ArH), 7.40 (m, 6H, ArH), 7.25 (s, 1H, ArH),7.10 (d, 1H, ArH), 5.70 (s, 2H, ArCH₂Het), 5.15 (s, 2H, ArCH₂O—). LC-MS:m/z 427 M+H⁺.

Example 42 1-(5-Bromo-2-Isobutoxy-Benzyl)-1H-Indazole-6-Carboxylic Acid,93

The title compound was prepared following the same method as Example 7.

¹H-NMR (DMSO, 300 MHz) δ 13.00 (s, 1H, COOH), 8.30 (s, 1H, ArH), 8.20(s, 1H, ArH), 7.85 (d, 1H, ArH), 7.70 (d, 1H, ArH), 7.40 (m, 1H, ArH),7.15 (s, 1H, ArH), 6.95 (d, 1H, ArH), 5.65 (s, 2H, ArCH₂Het), 3.70 (d,2H, —CH₂O—), 1.95 (m, 1H, CH), 0.85 (d, 6H, —CH₃). LC-MS: m/z 404 M+H⁺.

Example 43 2-(5-Bromo-2-Isobutoxy-Benzyl)-2H-Indazole-6-Carboxylic Acid,94

The title compound was prepared following the same method as Example 7.

¹H-NMR (CDCl₃, 300 MHz) δ 8.60 (s, 1H, ArH), 8.00 (s, 1H, ArH), 7.70 (m,2H, ArH), 7.40 (m, 1H, ArH), 7.25 (m, 1H, ArH), 6.75 (d, 1H, ArH), 5.65(s, 2H, ArCH₂Het), 3.75 (d, 2H, —CH₂O—), 2.10 (m, 1H, CH), 1.00 (d, 6H,—CH₃). LC-MS: m/z 404 M+H⁺.

Example 441-(5-Bromo-2-Cyclopentylmethoxy-Benzyl)-1H-Indazole-6-Carboxylic Acid,95

The title compound was prepared following the same method as Example 7.

¹H-NMR (CDCl₃, 300 MHz) δ 8.30 (s, 1H, ArH), 8.15 (s, 1H, ArH), 7.85 (q,2H, ArH), 7.30 (m, 1H, ArH), 7.05 (s, 1H, ArH), 6.75 (d, 1H, ArH), 5.65(s, 2H, ArCH₂Het), 3.87 (d, 2H, —CH₂O—), 2.45 (m, 1H, CH), 1.85 (m, 2H,—CH₂—CH₂—), 1.65 (m, 4H, —CH₂—CH₂—), 1.30 (m, 2H, —CH₂—CH₂—). LC-MS: m/z430 M+H⁺.

Example 452-(5-Bromo-2-Cyclopentylmethoxy-Benzyl)-2H-Indazole-6-Carboxylic Acid,96

The title compound was prepared following the same method as Example 7.

¹H-NMR (CDCl₃, 300 MHz) δ 8.65 (s, 1H, ArH), 8.00 (s, 1H, ArH), 7.70 (q,2H, ArH), 7.37 (m, 1H, ArH), 7.25 (m, 1H, ArH), 6.75 (d, 1H, ArH), 5.65(s, 2H, ArCH₂Het), 3.85 (d, 2H, —CH₂O—), 2.35 (m, 1H, CH), 1.80 (m, 2H,—CH₂—CH₂—), 1.55 (m, 4H, —CH₂—CH₂—), 1.30 (m, 2H, —CH₂—CH₂—). LC-MS: m/z430 M+H⁺.

Example 461-[5-Chloro-2-(2-Ethyl-Butoxy)-Benzyl]-1H-Indazole-6-Carboxylic Acid, 97

The title compound was prepared following the same method as Example 7.

¹H-NMR (CDCl₃, 300 MHz) δ 8.25 (s, 1H, ArH), 8.15 (s, 1H, ArH), 7.85 (q,2H, ArH), 7.15 (m, 1H, ArH), 6.80 (m, 2H, ArH), 5.65 (s, 2H, ArCH₂Het),3.90 (d, 2H, —CH₂O—), 1.75 (m, 1H, CH), 1.45 (q, 4H, —CH₂—CH₃), 0.95 (t,6H, —CH₂—CH₃). LC-MS: m/z 387 M+H⁺.

Example 471-(5-Chloro-3-Fluoro-2-Isobutoxy-Benzyl)-1H-Indazole-5-Carboxylic Acid,98

The title compound was prepared following the same method as Example 3but using (5-chloro-3-fluoro-2-methoxy-phenyl)-methanol as the startingmaterial.

¹H-NMR (CDCl₃, 300 MHz) δ 8.60 (s, 1H, ArH), 8.17 (m, 2H, ArH), 7.62 (d,1H, ArH), 7.14 (m, 1H, ArH), 6.90 (t, 1H, ArH), 5.74 (s, 2H, ArCH₂Het),3.76 (d, 2H, —CH₂O—), 2.11 (m, 1H, CH), 1.03 (d, 6H, —CH₃). LC-MS: m/z377 M+H⁺.

Example 481-(2-Isobutoxy-5-Methanesulfonyl-Benzyl)-1H-Indazole-5-Carboxylic Acid,99

The title compound was prepared following the same method as Example 3but using (5-methylsulphone-2-methoxy-phenyl)-methanol as the startingmaterial.

¹H-NMR (CDCl₃, 300 MHz) δ 8.53 (s, 1H, ArH), 8.14 (s, 1H, ArH), 8.03 (m,1H, ArH), 7.81 (m, 1H, ArH), 7.45 (m, 1H, ArH), 7.40 (d, 1H, ArH), 6.97(d, 1H, ArH), 5.61 (s, 2H, ArCH₂Het), 3.81 (d, 2H, —CH₂O—), 2.92 (s, 3H,SO₂CH₃), 2.05 (m, 1H, CH), 0.95 (d, 6H, —CH₃).

LC-MS: m/z 402 M+H⁺.

Example 49 1-(4,5-Dichloro-2-Isobutoxy-Benzyl)-1H-Indazole-5-CarboxylicAcid, 100

The title compound was prepared following the same method as Example 3but using (4,5-dichloro-2-methoxy-phenyl)-methanol as the startingmaterial.

¹H-NMR (CDCl₃, 300 MHz) δ 8.45 (s, 1H, ArH), 8.05 (m, 1H, ArH), 7.95 (d,1H, ArH), 7.31 (d, 1H, ArH), 6.83 (d, 2H, ArH), 5.45 (s, 2H, ArCH₂Het),3.65 (d, 2H, —CH₂O—), 1.98 (m, 1H, CH), 0.89 (d, 6H, —CH₃). LC-MS: m/z393 M+H⁺.

Example 501-(3-Isobutoxy-6-Methyl-Pyridin-2-Ylmethyl)-1H-Indazole-5-CarboxylicAcid, 104

Step 1 (3-Isobutoxy-6-methyl-pyridin-2-yl)-methanol, 101

A solution of 3-Hydroxy-2-(hydroxymethyl)-5-methyl-pyridine (1.0 g, 7.19mmole) in DMF (10 ml) was treated with potassium carbonate (5 g, 35.9mmole) and 1-iodo-2-methylpropane (1.65 ml, 14.4 mmole). The mixture wasstirred at room temperature under a nitrogen atmosphere for 18 h. Themixture was then evaporated to dryness and the residue partitionedbetween ethyl acetate (50 ml) and water (50 ml). The organic extract wasseparated then washed with saturated brine then dried over sodiumsulphate, filtered and evaporated to dryness. The residue waschromatographed on silica gel eluting with a 1:2 mixture of ethylacetate/isohexane. This gave the title compound as a pale yellow oil(0.62 g, 45%).

¹H-NMR (CDCl₃, 300 MHz) δ 7.02 (m, 2H, ArH), 4.73 (s, 2H, CH₂OH), 3.73(d, 2H, —OCH₂—), 2.50 (s, 3H, ArCH₃), 2.10 (m, 1H, CH), 1.03 (d, 6H,2×CH₃).

Step 2 Methanesulfonic acid 3-isobutoxy-6-methyl-pyridin-2-ylmethylester, 102

A solution of (3-Isobutoxy-6-methyl-pyridin-2-yl)-methanol (0.3 g, 1.54mmole) in dichloromethane (10 ml) was treated with diisopropylethylamine(0.3 ml, 1.69 mmole) and methanesulphonic anhydride (0.3 g, 1.69 mmole)then stirred at ambient temperature under a nitrogen atmosphere for 1.5h. The mixture was then washed with water (50 ml) and saturated brine(50 ml). The organic layer was dried over sodium sulphate, filtered andevaporated to dryness to give the title compound as a colorless oil.

1H-NMR (CDCl₃, 300 MHz) δ 7.15 (m, 2H, ArH), 5.41 (s, 2H, CH₂O Ms), 3.77(d, 2H, —OCH₂—), 3.11 (s, 3H, —OSOCH₃), 2.51 (s, 3H, ArCH₃), 2.15 (m,1H, CH), 1.06 (d, 6H, 2×CH₃).

Step 31-(3-Isobutoxy-6-methyl-pyridin-2-ylmethyl)-1H-indazole-5-carboxylicacid methyl ester, 103

To a solution of Methanesulfonic acid3-isobutoxy-6-methyl-pyridin-2-ylmethyl ester (1.54 mmole) and1H-Indazole-5-carboxylic acid methyl ester (0.247 g, 1.4 mmole) in DMF(8 ml) was added cesium carbonate (0.548 g, 1.68 mmole) and the mixturestirred at ambient temperature for 18 h. The mixture was evaporated todryness and the residue partitioned between water (20 ml) and ethylacetate (2×20 ml). The combined organics were dried over sodiumsulphate, filtered and evaporated to dryness. The residue waschromatographed using silica gel eluting with a 1:2 mixture of ethylacetate/isohexane to give in the early fractions the title compound(0.240 g, 48%) as a white solid. The corresponding 2-yl-indazole isomereluted in the later column fractions.

1H-NMR (CDCl₃, 300 MHz) δ 8.49 (s, 1H, ArH), 8.09 (s, 1H, ArH), 8.01(dd, 1H, ArH), 7.56 (d, 1H, ArH), 7.03 (s, 2H, ArH), 5.73 (s, 2H, CH₂),3.94 (s, 3H, CH₃), 3.62 (d, 2H, CH₂), 2.49 (s, 3H, CH₃), 1.94 (m, 1H,CH), 0.89 (d, 6H, 2×CH₃). LC-MS: m/z 354 M+H⁺.

Step 41-(3-Isobutoxy-6-methyl-pyridin-2-ylmethyl)-1H-indazole-5-carboxylicacid, 104

A solution of1-(3-Isobutoxy-6-methyl-pyridin-2-ylmethyl)-1H-indazole-5-carboxylicacid methyl ester (0.240 g, 0.68 mmole) in 1,4-dioxane (10 ml) wastreated with 2M sodium hydroxide (10 ml) and the mixture stirred at 60°C. for 18 h. The mixture was evaporated to dryness and the residuedissolved in water (20 ml) then acidified to pH1 with 2M hydrochloricacid. The resulting precipitate was extracted into ethyl acetate (2×50ml). The combined organics were dried over sodium sulphate, filtered andevaporated to dryness. The residue was chromatographed on silica geleluting a mixture 1:1 of isohexane/ethyl acetate to give the titlecompound as a white solid (0.2 g, 87%).

1H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.13 (s, 1H, ArH), 8.02(dd, 1H, ArH), 7.59 (d, 1H, ArH), 7.07 (s, 2H, ArH), 5.79 (s, 2H, CH₂),3.64 (d, 2H, CH₂), 2.49 (s, 3H, CH₃), 1.96 (m, 1H, CH), 0.90 (d, 6H,2×CH₃). LC-MS m/z 340 M+H⁺

Example 511-[5-Bromo-2-(1-Ethyl-Propoxy)-Benzyl]-1H-Indazole-5-Carboxylic Acid,105

The title compound was prepared following the same method as Example 4.

¹H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.10 (d,1H, ArH), 7.50 (d, 1H, ArH), 7.30 (m, 1H, ArH), 7.10 (s, 1H, ArH), 6.75(d, 1H, ArH), 5.55 (s, 2H, ArCH₂Het), 4.15 (m, 1H, —CHO—), 1.60 (q, 4H,CH₂), 0.80 (d, 6H, —CH₃).

LC-MS: m/z 418 M+H⁺.

Example 521-[5-Bromo-2-(2,2-Dimethyl-Propoxy)-Benzyl]-1H-Indazole-5-CarboxylicAcid, 106

The title compound was prepared following the same method as Example 4.

¹H-NMR (CDCl₃, 300 MHz) δ 8.57 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.10 (d,1H, ArH), 7.40 (d, 1H, ArH), 7.33 (m, 1H, ArH), 6.87 (s, 1H, ArH), 6.80(d, 1H, ArH), 5.65 (s, 2H, ArCH₂Het), 3.68 (s, 2H, CH₂), 1.05 (s, 9H,3×CH₃). LC-MS: m/z 418 M+H⁺.

Example 531-[5-Bromo-2-(2-Hydroxy-2-Methyl-Propoxy)-Benzyl]-1H-Indazole-5-CarboxylicAcid, 108

Step 11-[5-Bromo-2-(2-hydroxy-2-methyl-propoxy)-benzyl]-1H-indazole-5-carboxylicacid methyl ester, 107

A mixture of compound 12 (0.037 g, 0.1 mmole), 1.2-epoxy-2-methylpropane(0.1 mL, 1.1 mmol) and tetrabutylammonium fluoride 1M (0.1 mL, 0.1 mmol)in THF (3 ml) was treated under microwave conditions at 120° C. for 20min. Then methyl iodide (0.1 mL) and N-methylmorpholine (0.1 mL) wereadded to the solution and the mixture was treated under microwaveconditions at 120° C. for 10 minutes.

The mixture was diluted with methanol and ethyl acetate. Washed withwater and Brine. The organic extract was separated then dried oversodium sulphate, filtered and evaporated to dryness. The residue waschromatographed on silica gel eluting with a gradient from 1:4 to 2:3mixture of ethyl acetate/isohexane. This gave the title compound as apale yellow oil (0.03 g, 70%).

¹H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.15 (s, 1H, ArH), 8.10 (m,1H, ArH), 7.55 (d, 1H, ArH), 7.40 (m, 2H, ArH), 6.75 (d, 1H, ArH), 5.55(s, 2H, ArCH₂Het), 3.97 (s, 3H, CH₃), 3.80 (s, 2H, —CH₂O—), 1.40 (s, 6H,—CH₃).

Step 21-[5-bromo-2-(2-hydroxy-2-methyl-propoxy)-benzyl]-1h-indazole-5-carboxylicacid, 108

A solution of1-[5-Bromo-2-(2-hydroxy-2-methyl-propoxy)-benzyl]-1H-indazole-5-carboxylicacid methyl ester (0.03 g, 0.7 mmole) in a mixture of THF (5 ml),methanol (5 mL) and water (1 mL) was treated with lithium hydroxide (0.1g, 2.4 mmole) then stirred at ambient temperature under a nitrogenatmosphere for 20 h. The mixture was diluted with more water andextracted with isohexane. The aqueous layer was acidified with a 2M HClsolution and extracted with ethyl acetate. The organic layer was washedwith saturated brine (50 ml). The organic layer was dried over sodiumsulphate, filtered and evaporated to dryness to give the title compoundas a colorless oil.

¹H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.15 (s, 1H, ArH), 8.10 (m,1H, ArH), 7.55 (d, 1H, ArH), 7.40 (m, 2H, ArH), 6.75 (d, 1H, ArH), 5.55(s, 2H, ArCH₂Het), 3.80 (s, 2H, —CH₂O—), 1.40 (s, 6H, —CH₃). LC-MS: m/z420 M+H⁺.

Example 54 1-(5-Hydroxy-2-Isobutoxy-Benzyl)-1H-Indazole-5-CarboxylicAcid, 114

Step 1 5-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxy-benzoic acid methylester, 109

To a solution of methyl-2,5-dihydroxybenzoate (7.0 g, 41.7 mmole) andimidazole (4.24 g, 62.4 mmole), at 0° C. and under nitrogen, in DCM (300mL) was added a solution of tert-butyldimethylsilyl chloride (6.6 g,43.8 mmole) in DCM (60 mL) drop wise over 30 minutes. After 3 h, theice-bath was removed and the mixture was stirred at room temperature for16 h. Then the mixture was washed with 2M HCl solution and saturatedbrine then dried over sodium sulphate, filtered and evaporated todryness. This gave the title compound as colorless oil (11.1 g, 95%).

¹H-NMR (CDCl₃, 300 MHz) δ 10.3 (s, 1H, ArOH), 7.25 (m, 1H, ArH), 7.00(m, 1H, ArH), 6.85 (m, 1H, ArH), 3.95 (s, 3H, —OCH₃), 1.00 (s, 9H,SiC(CH₃)₃), 0.2 (s, 6H, 2×SiCH₃).

Step 2 5-(tert-Butyl-dimethyl-silanyloxy)-2-isobutoxy-benzoic acidmethyl ester, 110

A solution of 5-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxy-benzoic acidmethyl ester (5 g, 17.7 mmole) in anhydrous THF (150 ml) was treatedwith 2-methyl-1-propanol (1.8 ml, 19.5 mmole), triphenylphosphine (5.1g, 19.5 mmole) and DIAD (3.8 mL, 19.5 mmole) then stirred at 0° C. for 2h, at room temperature for 1 h and at reflux for 24 h. The mixture wasthen evaporated to dryness and the residue was purified by columnchromatography using 95:5 mixture of isohexane/ethyl acetate to give thetitle compound as a colorless oil. (1.8 g, 30%).

1H-NMR (CDCl₃, 300 MHz) δ 7.25 (m, 1H, ArH), 7.00 (m, 1H, ArH), 6.85 (m,1H, ArH), 3.85 (s, 3H, —OCH₃), 3.75 (d, 2H, OCH₂—), 2.10 (m, 1H, CH),1.05 (d, 6H, 2×CH₃), 1.00 (s, 9H, SiC(CH₃)₃), 0.2 (s, 6H, 2×SiCH₃).

Step 3 [5-(tert-Butyl-dimethyl-silanyloxy)-2-isobutoxy-phenyl]-methanol,111

To a solution 5-(tert-Butyl-dimethyl-silanyloxy)-2-isobutoxy-benzoicacid methyl ester (1.8 g, 5.32 mmole) in anhydrous toluene (50 ml) wasadded a 1M solution in toluene of DIBAL (21 mL, 21 mmole) and themixture stirred under nitrogen atmosphere at ambient temperature for 2h. Then a 10% Rochelle's salt solution was added and the mixture stirredfor 30 min more. 2M HCl solution (20 mL) was added and the mixture wasextracted with ethyl acetate. The combined organics were dried oversodium sulphate, filtered and evaporated to dryness. The residue waschromatographed using silica gel eluting with a 1:2 mixture of ethylacetate/isohexane to give in the early fractions the title compound(0.91 g, 55%) as a colorless oil.

1H-NMR (CDCl₃, 300 MHz) δ 6.75 (s, 1H, ArH), 6.55 (s, 2H, ArH), 4.52 (d,2H, —CH₂OH), 3.62 (d, 2H, OCH₂—), 2.10 (m, 1H, CH), 1.05 (d, 6H, 2×CH₃),1.00 (s, 9H, SiC(CH₃)₃), 0.2 (s, 6H, 2×SiCH₃). LC-MS: m/z 293 [M+H₂O]⁺.

Step 41-[5-(tert-Butyl-dimethyl-silanyloxy)-2-isobutoxy-benzyl]-1H-indazole-5-carboxylicacid methyl ester, 112

A solution of 1H-indazole-5-carboxylic acid methyl ester, 4, (0.6 g, 3.5mmole), triphenylphosphine (1.2 g, 4.4 mmole),[5-(tert-Butyl-dimethyl-silanyloxy)-2-isobutoxy-phenyl]-methanol (0.9 g,2.9 mmole) and di-isopropylazodicarboxylate (0.9 mL, 4.4 mmol) inanhydruous THF (50 mL) was heated at reflux for 16 h. Then the volatileswere removed in vacuo and the crude product was purified on silica usinga gradient from 95:5 to 90:10 isohexane/ethyl acetate. This gave thetitle compound as colorless oil (0.3 g, 20%).

¹H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.15 (s, 1H, ArH), 8.00 (d,1H, ArH), 7.40 (d, 1H, ArH), 6.70 (m, 2H, ArH), 6.25 (s, 1H, ArH), 5.52(s, 2H, —CH₂Het), 3.95 (s, 3H, OCH₃), 3.72 (d, 2H, OCH₂—), 2.10 (m, 1H,CH), 1.05 (d, 6H, 2×CH₃), 0.85 (s, 9H, SiC(CH₃)₃), 0.05 (s, 6H,2×SiCH₃).

Step 5 1-(5-Hydroxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic acidmethyl ester, 113

A solution of1-[5-(tert-Butyl-dimethyl-silanyloxy)-2-isobutoxy-benzyl]-1H-indazole-5-carboxylicacid methyl ester (0.3 g, 0.64 mmole) in anhydruous THF (10 mL) wastreated with a 1M TBAF solution in THF (1 mL, 1 mmole) and the mixturewas stirred at room temperature for 1 h. Then the volatiles were removedin vacuo and the crude product was purified on silica using a gradientfrom 4:1 to 3:1 isohexane/ethyl acetate. This gave the title compound ascolorless oil (0.135 g, 60%).

¹H-NMR (CDCl₃, 300 MHz) δ 8.50 (s, 1H, ArH), 8.02 (d, 1H, ArH), 7.90 (s,1H, ArH), 7.40 (d, 1H, ArH), 6.70 (m, 2H, ArH), 6.20 (s, 1H, ArH), 6.10(s, 1H, ArOH), 5.60 (s, 2H, —CH₂Het), 3.97 (s, 3H, OCH₃), 3.75 (d, 2H,OCH₂—), 2.10 (m, 1H, CH), 1.05 (d, 6H, 2×CH₃).

Step 6 1-(5-Hydroxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid,114

A solution of 11-(5-Hydroxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylicacid methyl ester (0.03 g, 0.08 mmole) in a mixture of THF (2 ml),methanol (1 mL) and water (1 mL) was treated with lithium hydroxide(0.09 g, 2.14 mmole) then stirred under microwave conditions at 120° C.for 5 min. The mixture was diluted with more water and extracted withisohexane. The aqueous layer was acidified with a 2M HCl solution andextracted with ethyl acetate. The organic layer was washed withsaturated brine (50 ml). The organic layer was dried over sodiumsulphate, filtered and evaporated to dryness to give the crude residuethat was purified by column in silica using 1:1 mixture ethylacetate/isohexane as eluent to give the title compound as a colorlessoil. (12.3 mg, 50%).

¹H-NMR (MeOD, 300 MHz) δ 8.55 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.12 (d,1H, ArH), 7.55 (d, 1H, ArH), 6.80 (m, 1H, ArH), 6.75 (m, 1H, ArH), 6.25(s, 1H, ArH), 5.60 (s, 2H, —CH₂Het), 3.70 (d, 2H, OCH₂—), 2.10 (m, 1H,CH), 1.00 (d, 6H, 2×CH₃). LC-MS: m/z 341 M+H⁺.

Example 551-[5-(2,2-Difluoro-Ethoxy)-2-Isobutoxy-Benzyl]-1H-Indazole-5-CarboxylicAcid, 116

Step 11-[5-(2,2-Difluoro-ethoxy)-2-isobutoxy-benzyl]-1H-indazole-5-carboxylicacid methyl ester, 115

A solution of compound 104 (0.03 g, 0.08 mmole) in a mixture ofanhydrous THF (2 ml) and anhydrous toluene (1 mL) was treated with2,2-difluoroethanol (0.04 ml, 0.27 mmole), triphenylphosphine (0.07 g,0.27 mmole) and DTAD (0.055 g, 0.27 mmole) then stirred under microwaveconditions at 140° C. for 20 min. The mixture was then evaporated todryness and the residue was purified by column chromatography using agradient from 90:10 to 80:20 mixture of isohexane/ethyl acetate to givethe title compound as a colorless oil. (0.02 g, 60%).

1H-NMR (CDCl₃, 300 MHz) δ 8.55 (s, 1H, ArH), 8.15 (s, 1H, ArH), 8.02 (d,1H, ArH), 7.45 (d, 1H, ArH), 6.75 (m, 2H, ArH), 6.45 (s, 1H, ArH), 5.97(tt, 1H, F₂CH), 5.65 (s, 2H, —CH₂Het), 4.00 (m, 2H, CH₂CHF₂), 3.95 (s,3H, OCH₃), 3.75 (d, 2H, OCH₂—), 2.10 (m, 1H, CH), 1.05 (d, 6H, 2×CH₃).

Step 21-[5-(2,2-Difluoro-ethoxy)-2-isobutoxy-benzyl]-1H-indazole-5-carboxylicacid, 116

A solution of1-[5-(2,2-Difluoro-ethoxy)-2-isobutoxy-benzyl]-1H-indazole-5-carboxylicacid methyl ester (0.02 g, 0.05 mmole) in a mixture of THF (3 ml),methanol (4 mL) and water (1 mL) was treated with lithium hydroxide (0.1g, 2.4 mmole) then stirred at room temperature for 16 h. The mixture wasdiluted with more water and extracted with isohexane. The aqueous layerwas acidified with a 2M HCl solution and extracted with ethyl acetate.The organic layer was washed with saturated brine (50 ml). The organiclayer was dried over sodium sulphate, filtered and evaporated to drynessto give the title compound as a colorless oil. (19.2 mg, 95%).

¹H-NMR (CDCl₃, 300 MHz) δ 8.60 (s, 1H, ArH), 8.17 (s, 1H, ArH), 8.05 (d,1H, ArH), 7.45 (d, 1H, ArH), 6.77 (m, 2H, ArH), 6.50 (s, 1H, ArH), 5.97(tt, 1H, F₂CH), 5.65 (s, 2H, —CH₂Het), 4.00 (td, 2H, CH₂CHF₂), 3.75 (d,2H, OCH₂—), 2.10 (m, 1H, CH), 1.05 (d, 6H, 2×CH₃). LC-MS: m/z 405 M+H⁺

Example 561-(5-Difluoromethoxy-2-Isobutoxy-Benzyl)-1H-Indazole-5-Carboxylic Acid,118

Step 1 1-(5-Difluoromethoxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylicacid methyl ester, 117

To a solution of compound 104 (0.07 g, 0.2 mmole) in acetonitrile (1.5ml) was added an aqueous solution of KOH in water (4 mmole in 1.5 mL).Nitrogen was bubbled through the mixture for 5 min. and then cold downto −78° C. under nitrogen atmosphere. Then the mixture was treated witha solution of diethyl(bromodifluoromethyl)phosphonate (0.074 ml, 0.4mmole) in acetonitrile (0.3 mL), allowed to warm to room temperatureslowly (20 min) and stirred for 1.5 h. Then, the same process wasrepeated again but this time the reaction was stirred overnight.

To the reaction mixture was added ethyl acetate and 2M HCl solution. Theorganic layer was separated, washed with Brine, dried and thenevaporated to dryness. The residue was purified by column chromatographyusing a gradient from 100:0 to 90:10 mixture of isohexane/ethyl acetateto give the title compound as a colorless oil. (0.014 g, 17%).

¹H-NMR (CDCl₃, 300 MHz) δ 8.65 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.08 (d,1H, ArH), 7.45 (d, 1H, ArH), 7.00 (m, 1H, ArH), 6.85 (d, 1H, ArH), 6.55(s, 1H, ArH), 6.3 (t, 1H, F₂CH), 5.65 (s, 2H, —CH₂Het), 3.95 (s, 3H,OCH₃), 3.78 (d, 2H, OCH₂—), 2.10 (m, 1H, CH), 1.05 (d, 6H, 2×CH₃).

Step 2 1-(5-Difluoromethoxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylicacid, 118

A solution of1-(5-Difluoromethoxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic acidmethyl ester (0.014 g, 0.035 mmole) in a mixture of THF (1 ml), methanol(1 mL) and water (1 mL) was treated with lithium hydroxide (0.05 g, 1.2mmole) then stirred at room temperature for 16 h. The mixture wasdiluted with more water and extracted with isohexane. The aqueous layerwas acidified with a 2M HCl solution and extracted with ethyl acetate.The organic layer was washed with saturated brine (50 ml). The organiclayer was dried over sodium sulphate, filtered and evaporated to drynessto give the title compound as a colorless oil. (8.7 mg, 63%).

1H-NMR (CDCl₃, 300 MHz) δ 8.65 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.08 (d,1H, ArH), 7.45 (d, 1H, ArH), 7.00 (m, 1H, ArH), 6.85 (d, 1H, ArH), 6.55(s, 1H, ArH), 6.3 (t, 1H, F₂CH), 5.65 (s, 2H, —CH₂Het), 3.78 (d, 2H,OCH₂—), 2.10 (m, 1H, CH), 1.05 (d, 6H, 2×CH₃). LC-MS: m/z 391 M+H⁺.

Example 571-(5-Chloro-2-Isobutoxy-Benzyl)-1H-Pyrazolo[3,4-b]Pyridine-5-CarboxylicAcid, 119

The title compound was prepared following the same method as Example 30.

¹H-NMR (CDCl₃, 300 MHz) δ 9.25 (s, 1H, ArH), 8.80 (s, 1H, ArH), 8.20 (s,1H, ArH), 7.33 (m, 2H, ArH), 6.74 (d, 1H, ArH), 5.65 (s, 2H, ArCH₂),3.75 (d, 2H, OCH₂). 2.01 (m, 1H, CH), 0.96 (d, 6H, CH₃). LC-MS: m/z 360M+H⁺.

Example 581-(2-Isobutoxy-5-Trifluoromethoxy-Benzyl)-1H-Pyrazolo[3,4-b]Pyridine-5-CarboxylicAcid, 120

The title compound was prepared following the same method as Example 30.

¹H-NMR (CDCl₃, 300 MHz) δ 9.25 (s, 1H, ArH), 8.70 (s, 1H, ArH), 8.00 (s,1H, ArH), 7.05 (m, 1H, ArH), 6.75 (d, 1H, ArH), 6.65 (s, 1H, ArH), 5.65(s, 2H, ArCH₂), 3.65 (d, 2H, OCH₂). 2.01 (m, 1H, CH), 0.96 (d, 6H, CH₃).LC-MS: m/z 410 M+H⁺.

Example 591-[5-Bromo-2-(2-Ethyl-Butoxy)-Benzyl]-3-Methyl-1H-Pyrazolo[3,4-b]Pyridine-5-CarboxylicAcid, 121

The title compound was prepared following the same method as Example 30.

¹H-NMR (CDCl₃, 300 MHz) δ 9.22 (s, 1H, ArH), 8.80 (s, 1H, ArH), 7.32 (s,1H, ArH), 6.85 (m, 1H, ArH), 6.75 (d, 1H, ArH), 5.70 (s, 2H, ArCH₂),3.88 (d, 2H, OCH₂). 2.65 (s, 3H, ArCH₃), 2.01 (m, 1H, CH), 1.45 (q, 4H,2×CH₂), 0.96 (t, 6H, 2×CH₃).

LC-MS: m/z 448 M+H⁺.

Example 601-[5-Chloro-2-(2-Ethyl-Butoxy)-Benzyl]-3-Methyl-1H-Pyrazolo[3,4-b]Pyridine-5-CarboxylicAcid, 122

The title compound was prepared following the same method as Example 30.

¹H-NMR (CDCl₃, 300 MHz) δ 9.22 (s, 1H, ArH), 8.80 (s, 1H, ArH), 7.15 (m,1H, ArH), 6.80 (d, 1H, ArH), 6.70 (d, 1H, ArH), 5.65 (s, 2H, ArCH₂),3.88 (d, 2H, OCH₂). 2.65 (s, 3H, ArCH₃), 2.01 (m, 1H, CH), 1.45 (q, 4H,2×CH₂), 0.96 (t, 6H, 2×CH₃).

LC-MS: m/z 402 M+H⁺.

Example 611-(5-Chloro-2-Isobutoxy-Benzyl)-3-Methyl-1H-Pyrazolo[3,4-b]Pyridine-5-CarboxylicAcid, 123

The title compound was prepared following the same method as Example 30.

¹H-NMR (CDCl₃, 300 MHz) δ 9.25 (s, 1H, ArH), 8.70 (s, 1H, ArH), 7.15 (d,1H, ArH), 6.75 (d, 1H, ArH), 6.15 (d, 1H, ArH), 5.65 (s, 2H, ArCH₂),3.70 (d, 2H, OCH₂). 2.65 (s, 3H, ArCH₃), 2.01 (m, 1H, CH), 0.90 (d, 6H,2×CH₃).

LC-MS: m/z 374 M+H⁺

Example 621-[5-Chloro-2-(2-Ethyl-Butoxy)-Benzyl]-1H-Pyrazolo[3,4-c]Pyridine-5-CarboxylicAcid Amide, 129

Step 1 1H-Pyrazolo[3,4-c]pyridine-5-carbonitrile, 124

A mixture of 5-Bromo-1,4-pyrazolo[3,4,c]pyridine (0.15 g, 0.76 mmole),Zn(CN)₂ (0.092 g, 0.76 mmole) and Pd(PPh₃)₄ (0.026 g, 0.02 mmole) in DMF(2 ml) heated at 180° C. in a microwave reactor under a N₂ atmospherefor 30 min. The mixture was partitioned between water and EtOAc. Theorganic layer was washed with brine, dried (MgSO₄) and evaporated todryness to give the title compound as a brown solid.

¹H-NMR (MeOD, 300 MHz) δ 8.35 (s, 1H, ArH), 7.38 (s, 1H, ArH), 7.28 (s,1H, ArH).

Step 2 5-chloro-2-(2-ethyl-butoxy)-benzaldehyde, 125

A solution of 5-chloroalicaldehyde (2.0 g, 12.8 mmole) in DMF (50 ml)was treated with potassium carbonate (3 g, 22 mmole) andtetrabutylammonium iodide (0.22 g) and 3-chloromethylpentane (1.65 ml,12.2 mmole). The mixture was stirred at 110° C. under a nitrogenatmosphere for 18 h. The mixture was then evaporated to dryness and theresidue partitioned between ethyl acetate (50 ml) and water (50 ml). Theorganic extract was separated then washed with saturated brine thendried over sodium sulphate, filtered and evaporated to dryness. Theresidue was chromatographed on silica gel eluting with a gradient of5-15% ethyl acetate/isohexane. This gave the title compound as a paleyellow oil (2.97 g, 78%).

¹H-NMR (CDCl₃, 300 MHz) δ10.49 (s, 1H, CHO), 7.95 (d, 1H, ArH), 7.63(dd, 1H, ArH), 6.90 (d, 1H, ArH), 4.00 (d, 2H, CH₂), 1.80 (m, 1H, CH),1.55 (s, 4H, 2×CH₂—CH₃), 1.00 (q, 6H, 2×CH₂—CH₃).

Step 3 [5-Chloro-2-(2-ethyl-butoxy)-phenyl]methanol, 126

The title compound was prepared following the method in Example 20, Step2.

¹H-NMR (CDCl₃, 300 MHz) δ7.45 (d, 1H, ArH), 7.37 (dd, 1H, ArH), 6.80 (d,1H, ArH), 4.70 (d, 2H, —CH₂OH), 3.90 (d, 2H, CH₂), 1.80 (m, 1H, CH),1.55 (s, 4H, 2×CH₂—CH₃), 1.00 (q, 6H, 2×CH₂—CH₃).

Step 4 Methanesulfonic acid 5-chloro-2-(2-ethyl-butoxy)-benzyl ester,127

The title compound was prepared following the method in Example 20, Step3.

¹H-NMR (CDCl₃, 300 MHz) δ7.55 (d, 1H, ArH), 7.45 (dd, 1H, ArH), 6.80 (d,1H, ArH), 5.75 (d, 2H, —CH₂OSO₂CH₃), 3.90 (d, 2H, CH₂), 3.00 (s, 3H,CH₂OSO₂CH₃), 1.80 (m, 1H, CH), 1.55 (s, 4H, 2×CH₂—CH₃), 1.00 (q, 6H,2×CH₂—CH₃).

Step 51-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile,128

The title compound was prepared following the method in Example 21, Step4.

¹H-NMR (CDCl₃, 300 MHz) δ 8.95 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.10 (s,1H, ArH), 7.25 (m, 1H, ArH), 7.05 (s, 1H, ArH), 6.85 (s, 1H, ArH), 5.65(s, 2H, ArCH₂), 3.85 (d, 2H, CH₂). 1.65 (m, 1H, CH), 1.35 (q, 4H,2×CH₂), 0.85 (t, 6H, 2×CH₃).

LC-MS: m/z 369 M+H⁺

Step 61-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylicacid amide, 129

A mixture of1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile(0.048 g, 0.13 mmole), 5M aqueous solution of KOH (1 mL), PEG-400 (0.5mL) and dioxane (0.5 mL) was heated at 180° C. under microwaveconditions for 30 min. The mixture was diluted with ethyl acetate (6 mL)and 2M HCl solution (6 mL) and the reaction mixture was extracted. Theorganic layer was separated, washed with Brine, dried (MgSO₄), filteredand the solvent evaporated under vacuum. The residue was purified insilica using 3:2 mixture of isohexane/ethyl acetate to give the titlecompound as a colorless oil. (0.024 mg, 48%).

¹H-NMR (CDCl₃, 300 MHz) δ 9.12 (s, 1H, ArH), 8.50 (s, 1H, ArH), 8.07 (s,1H, ArH), 7.30 (m, 1H, ArH), 7.22 (s, 1H, ArH), 6.85 (d, 1H, ArH), 5.75(s, 2H, ArCH₂), 3.80 (d, 2H, CH₂). 1.50 (m, 1H, CH), 1.25 (q, 4H,2×CH₂), 0.80 (t, 6H, 2×CH₃).

LC-MS: m/z 387 M+H⁺

Example 631-[5-Chloro-2-(2-Ethyl-Butoxy)-Benzyl]-1H-Pyrazolo[3,4-c]Pyridine-5-CarboxylicAcid, 130

A mixture of1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazolo[3,4-c]pyridine-5-carboxylicacid amide (0.019 g, 0.05 mmole), concentrated solution of HCl (1 mL)and dioxane (0.5 mL) was heated at 150° C. under microwave conditionsfor 30 min. The mixture was diluted with ethyl acetate (6 mL) and 2M HClsolution (6 mL) and the reaction mixture was extracted. The aqueousphase was basified to PH 5-6 with 2M solution of NaOH and extractedagain with ethyl acetate. The combined organic layers were washed withBrine, dried (MgSO₄), filtered and the solvent evaporated under vacuum.The residue was purified in a RP-HPLC to give the title compound as acolorless oil. (0.01 mg, 58%).

¹H-NMR (MeOD, 300 MHz) δ 9.05 (s, 1H, ArH), 8.52 (s, 1H, ArH), 8.30 (s,1H, ArH), 7.30 (m, 1H, ArH), 7.25 (s, 1H, ArH), 6.95 (d, 1H, ArH), 5.65(s, 2H, ArCH₂), 3.85 (d, 2H, CH₂). 1.52 (m, 1H, CH), 1.35 (q, 4H,2×CH₂), 0.85 (t, 6H, 2×CH₃).

LC-MS: m/z 388 M+H⁺

Example 641-(5-Bromo-2-Isobutoxy-Benzyl)-3-Ethyl-1H-Indazole-5-Carboxylic Acid,134

Step 1 3-Vinyl-1H-indazole-5-carboxylic acid methyl ester, 131

3-Iodo-1H-indazole-5-carboxylic acid methyl ester (0.5 g, 1.65 mmole) indimethoxyethane (12.5 ml) was placed in a microwave vial and treatedwith sodium carbonate (0.55 g, 5.1 mmole),tetrakis(triphenylphosphine)palladium(0) (0.09 g, 5 mol %) andvinylboronicanhydride pyridine complex (0.96 g, 4 mmole). The mixturewas heated in a microwave at 160° C. (very high absorbance setting) for1 hour. After cooling the mixture was partitioned between water (50 ml)and ethyl acetate (3×50 ml). The combined organic extracts were thenwashed with saturated brine (50 ml), separated and dried over sodiumsulphate, filtered and evaporated to dryness. The residue waschromatographed on silica eluting with a gradient of 20-60% ethylacetate/isohexane to give the title compound as a white solid (0.134 g).

¹H-NMR (CDCl₃, 300 MHz) δ 10.45-11.05 (brs, 1H, NH), 8.71 (s, 1H, ArH),8.12 (d, 1H, ArH), 7.47 (d, 1H, ArH), 7.12 (dd, 1H, CH), 6.25 (d, 1H,CH), 5.67 (d, 1H, CH), 3.97 (s, 3H, CH₃)

Step 2 3-Ethyl-1H-indazole-5-carboxylic acid methyl ester, 132

3-Vinyl-1H-indazole-5-carboxylic acid methyl ester (0.134 g, 0.66 mmole)in ethanol (10 ml) was hydrogenated at atmospheric pressure over 10%palladium on charcoal at ambient temperature for 20 hours. The mixturewas then filtered through celite washing with ethanol. The combinedfiltrates were evaporated to dryness to give the title compound as apale yellow oil (0.118 g).

¹H-NMR (CDCl₃, 300 MHz) δ 10.71-11.02 (brs, 1H, NH), 8.51 (s, 1H, ArH),8.05 (d, 1H, ArH), 7.45 (d, 1H, ArH), 3.97 (s, 3H, CH₃), 3.03 (q, 2H,CH₂), 1.45 (t, 3H, CH₃).

Step 3 1-(5-bromo-2-isobutoxy-benzyl)-3-ethyl-1h-indazole-5-carboxylicacid methyl ester, 133

The titled compound was prepared following the method described inExample 21, step 4.

¹H-NMR (CDCl₃, 300 MHz) δ 8.62 (s, 1H, ArH), 8.09 (dd, 1H, ArH), 7.39(d, 1H, ArH), 7.34 (dd, 1H, ArH), 6.95 (d, 1H, ArH), 6.77 (d, 1H, ArH),5.57 (s, 2H, CH₂), 3.97 (s, 3H, OCH₃), 3.77 (d, 2H, CH₂), 3.08 (q, 2H,CH₂), 2.07-2.18 (m, 1H, CH), 1.48 (t, 3H, CH₃), 1.05 (d, 6H, 2×CH₃).

Step 4 1-(5-bromo-2-isobutoxy-benzyl)-3-ethyl-1h-indazole-5-carboxylicacid, 134

The titled compound was prepared following the method described inExample 20, step 5.

¹H-NMR (CDCl₃, 300 MHz) δ 8.62 (s, 1H, ArH), 8.09 (dd, 1H, ArH), 7.39(d, 1H, ArH), 7.34 (dd, 1H, ArH), 6.95 (d, 1H, ArH), 6.77 (d, 1H, ArH),5.57 (s, 2H, CH₂), 3.77 (d, 2H, CH₂), 3.08 (q, 2H, CH₂), 2.07-2.18 (m,1H, CH), 1.48 (t, 3H, CH₃), 1.05 (d, 6H, 2×CH₃).

Example 651-[5-Bromo-2-(2-Ethyl-Butoxy)-Benzyl]-3-Ethyl-1H-Indazole-5-CarboxylicAcid, 135

The title compound was prepared following the same method as Example 64but using Compound 80 as the starting material.

H-NMR (CDCl₃, 300 MHz) δ 8.61 (s, 1H, ArH), 8.09 (d, 1H, ArH), 7.32-7.39(m, 2H, 2×ArH), 6.92 (d, 1H, ArH), 6.77 (d, 1H, ArH), 5.58 (s, 2H, CH₂),3.88 (d, 2H, CH₂), 3.08 (q, 2H, CH₂), 1.65-1.77 (m, 1H, CH), 1.41-1.53(m, 7H, 2×CH₂+CH₃), 0.95 (t, 6H, 2×CH₃).

Example 661-(5-Bromo-2-Isobutoxy-Benzyl)-2-Methyl-1H-Indole-5-Carboxylic Acid, 136

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 8.41 (s, 1H, ArH), 7.92 (s, 1H, ArH), 7.28(dd, 1H, ArH), 7.21 (d, 1H, ArH), 6.78 (d, 1H, ArH), 6.49 (s, 1H, ArH),6.41 (d, 1H, ArH), 5.31 (s, 2H, CH₂), 3.81 (d, 2H, CH₂), 2.38 (s, 3H,CH₃), 2.15-2.25 (m, 1H, CH), 1.11 (d, 6H, 2×CH₃).

Example 67 1-(5-Bromo-2-Isobutoxy-Benzyl)-1H-Indole-5-Carboxylic Acid,137

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 8.51 (s, 1H, ArH), 7.99 (d, 1H, ArH), 7.35 (d,1H, ArH), 7.31 (dd, 1H, ArH), 7.21 (d, 1H, ArH), 6.97 (d, 1H, ArH), 6.75(d, 1H, ArH), 6.65 (d, 1H, ArH), 5.31 (s, 2H, CH₂), 3.77 (d, 2H, CH₂),2.08-2.31 (m, 1H, CH), 1.04 (d, 6H, 2×CH₃).

Example 681-[5-Bromo-2-(2-Ethyl-Butoxy)-Benzyl]-2-Methyl-1H-Indole-5-CarboxylicAcid, 138

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 8.45 (s, 1H, ArH), 7.91 (d, 1H, ArH), 7.29(dd, 1H, ArH), 7.19 (d, 1H, ArH), 6.81 (d, 1H, ArH), 6.47 (s, 1H, ArH),6.38 (s, 1H, ArH), 5.29 (s, 2H, CH₂), 3.95 (d, 2H, CH₂), 2.38 (s, 3H,CH₃), 1.81-1.92 (m, 1H, CH), 1.48-1.62 (m, 4H, 2×CH₂), 0.97 (t, 6H,2×CH₃).

Example 69 1-[5-Bromo-2-(2-Ethyl-Butoxy)-Benzyl]-1H-Indole-5-CarboxylicAcid, 139

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 8.52 (s, 1H, ArH), 7.99 (d, 1H, ArH), 7.35 (d,1H, ArH), 7.31 (d, 1H, ArH), 7.19 (d, 1H, ArH), 6.91 (d, 1H, ArH), 6.82(d, 1H, ArH), 6.69 (d, 1H, ArH), 5.32 (s, 2H, CH₂), 3.91 (d, 2H, CH₂),1.62-1.74 (m, 1H, CH), 1.39-1.51 (m, 4H, 2×CH₂), 0.93 (t, 6H, 2×CH₃).

Example 70 1-[5-Bromo-2-(2-Ethyl-Butoxy)-Benzyl]-1H-Indole-6-CarboxylicAcid, 140

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 8.22 (s, 1H, ArH), 7.91 (d, 1H, ArH), 7.71 (d,1H, ArH), 7.35 (dd, 1H, ArH), 7.27 (d, 1H, ArH), 6.85 (d, 1H, ArH), 6.81(d, 1H, ArH), 6.63 (d, 1H, ArH), 5.37 (s, 2H, CH₂), 3.93 (d, 2H, CH₂),1.65-1.78 (m, 1H, CH), 1.41-1.52 (m, 4H, 2×CH₂), 0.94 (t, 6H, 2×CH₃)

Example 711-(2-Isobutoxy-5-Trifluoromethoxy-Benzyl)-1H-Indole-5-Carboxylic Acid,141

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 8.53 (s, 1H, ArH), 7.97 (d, 1H, ArH), 7.35 (d,1H, ArH), 7.22 (d, 1H, ArH), 7.13 (dd, 1H, ArH), 6.96 (d, 1H, ArH), 6.68(d, 1H, ArH), 6.61 (s, 1H, ArH), 5.35 (s, 2H, CH₂), 3.79 (d, 2H, CH₂),2.07-2.21 (m, 1H, CH), 0.94 (d, 6H, 2×CH₃).

Example 721-(5-Bromo-2-Isobutoxy-Benzyl)-1H-Pyrrolo[2,3-b]Pyridine-5-CarboxylicAcid, 142

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 9.13 (s, 1H, ArH), 8.65 (s, 1H, ArH), 7.36(dd, 1H, ArH), 7.29 (d, 1H, ArH), 7.13 (d, 1H, ArH), 6.75 (d, 1H, ArH),6.61 (d, 1H, ArH), 5.53 (s, 2H, CH₂), 3.75 (d, 2H, CH₂), 2.01-2.18 (m,1H, CH), 1.02 (d, 6H, 2×CH₃).

Example 731-(5-Bromo-2-Isobutoxy-Benzyl)-1H-Pyrrolo[3,2-b]Pyridine-5-CarboxylicAcid, 143

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 8.09 (d, 1H, ArH), 7.81 (d, 1H, ArH), 7.55 (d,1H, ArH), 7.39 (dd, 1H, ArH), 6.99 (d, 1H, ArH), 6.81 (s, 1H, ArH), 6.78(d, 1H, ArH), 5.33 (s, 2H, CH₂), 3.74 (d, 2H, CH₂), 1.98-2.12 (m, 1H,CH), 0.99 (d, 6H, 2×CH₃).

Example 741-(2-Isobutoxy-5-Trifluoromethoxy-Benzyl)-1H-Pyrrolo[2,3-b]Pyridine-5-CarboxylicAcid, 144

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 8.99 (s, 1H, ArH), 8.61 (s, 1H, ArH), 7.23 (d,1H, ArH), 7.05 (dd, 1H, ArH), 6.81 (d, 1H, ArH), 6.78 (s, 1H, ArH), 6.54(d, 1H, ArH), 5.47 (s, 2H, CH₂), 3.75 (d, 2H, CH₂), 1.98-2.12 (m, 1H,CH), 0.97 (d, 6H, 2×CH₃).

Example 751-(2-Isobutoxy-5-Trifluoromethoxy-Benzyl)-3-Methyl-1H-Indole-5-CarboxylicAcid, 145

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 8.48 (s, 1H, ArH), 7.97 (dd, 1H, ArH), 7.31(d, 1H, ArH), 7.11 (dd, 1H, ArH), 6.95 (s, 1H, ArH), 6.85 (d, 1H, ArH),6.61 (d, 1H, ArH), 5.28 (s, 2H, CH₂), 3.75 (d, 2H, CH₂), 2.48 (s, 3H,CH₃), 2.06-2.21 (m, 1H, CH), 1.05 (d, 6H, 2×CH₃).

Example 761-[2-(2-Ethyl-Butoxy)-5-Trifluoromethoxy-Benzyl]-1H-Pyrrolo[2,3-b]Pyridine-5-CarboxylicAcid, 146

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 9.11 (d, 1H, ArH), 8.71 (d, 1H, ArH), 7.29 (d,1H, ArH), 7.11 (dd, 1H, ArH), 6.85-6.91 (m, 2H, 2×ArH), 6.61 (d, 1H,ArH), 5.55 (s, 2H, CH₂), 3.92 (d, 2H, CH₂), 1.59-1.71 (m, 1H, CH),1.37-1.48 (m, 4H, 2×CH₂), 0.89 (t, 6H, 2×CH₃).

Example 771-[2-(2-Ethyl-Butoxy)-5-Trifluoromethoxy-Benzyl]-3-Methyl-1H-Indole-5-CarboxylicAcid, 147

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 8.45 (s, 1H, ArH), 7.95 (d, 1H, ArH), 7.28 (d,1H, ArH), 7.11 (dd, 1H, ArH), 6.93 (s, 1H, ArH), 6.88 (d, 1H, ArH), 6.65(d, 1H, ArH), 5.25 (s, 2H, CH₂), 3.93 (d, 2H, CH₂), 2.41 (s, 3H, CH₃),1.62-1.75 (m, 1H, CH), 1.41-1.53 (m, 4H, 2×CH₂), 0.93 (t, 6H, 2×CH₃).

Example 781-[5-Bromo-2-(2-Ethyl-Butoxy)-Benzyl]-1H-Benzoimidazole-5-CarboxylicAcid, 148

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 8.59 (s, 1H, ArH), 8.07 (dd, 1H, ArH), 8.02(s, 1H, ArH), 7.39-7.47 (m, 2H, 2×ArH), 7.19 (d, 1H, ArH), 6.82 (d, 1H,ArH), 5.31 (s, 2H, CH₂), 3.87 (d, 2H, CH₂), 1.59-1.69 (m, 1H, CH),1.33-1.45 (m, 4H, 2×CH₂), 0.88 (t, 6H, 2×CH₃).

Example 79 1-(5-Bromo-2-Isobutoxy-Benzyl)-1H-Benzoimidazole-5-CarboxylicAcid, 149

The title compound was prepared following the same method as Example 21.

¹H-NMR (CDCl₃, 300 MHz) δ 8.51 (s, 1H, ArH), 8.03 (s, 1H, ArH), 8.01(dd, 1H, ArH), 7.37-7.46 (m, 2H, 2×ArH), 7.19 (d, 1H, ArH), 6.78 (d, 1H,ArH), 5.31 (s, 2H, CH₂), 3.71 (d, 2H, CH₂), 1.97-2.09 (m, 1H, CH), 0.88(d, 6H, 2×CH₃).

While the Examples, above, demonstrate the preparation of certain indoleand indazole compounds, isoindoles, as well as other aza compounds mayalso be prepared by analogous methods as those shown in the Examples.

The above compounds were tested for PG antagonist activity as followsusing human recombinant prostanoid receptor (DP₁, EP₁₋₄, FP, IP and TP)stable cell lines: In order to measure the response of G_(s) and G_(i)coupled prostanoid receptors as a Ca²⁺ signal, chimeric G protein cDNAswere used. Stable cell lines over-expressing human prostanoid DP₁,EP₁₋₄, FP, IP, and TP receptors were established as follows:

Briefly, human prostanoid DP₁, EP₂, and EP₄ receptor cDNAs wereco-transfected with chimeric G_(qs) cDNA containing a haemagglutanin(HA) epitope; human prostanoid EP₃ receptors were co-transfected withchimeric G_(qi)-HA; human EP₁, FP, IP, and TP receptor cDNAs wereexpressed with no exogenous G-proteins. G_(qs) and G_(qi) chimeric cDNAs(Molecular Devices, Sunnyvale, Calif., U.S.A.), as well as cDNAs ofprostanoid receptors, were cloned into a pCEP₄ vector with a hygromycinB selection marker. Transfection into HEK-293 EBNA (Epstein-Barr virusnuclear antigen) cells was achieved by the FuGENE 6 transfection Reagent(Roche Applied Science, Indianapolis, Ind., USA). Stable transfectantswere selected according to hygromycin resistance. Because G_(qs) andG_(qi) contained an HA epitope, G-protein expression was detected byWestern blotting analysis using anti-mouse HA monoclonal antibody andhorseradish peroxidase (HRP)-conjugated secondary antibody, whilefunctional expression of prostanoid receptors was detected by FLIPRscreening (Matias et al., 2004). These stable cell lines were validatedusing previously published antagonists at 10 μM against serial dilutionsof standard agonists by FLIPR functional assays for Ca²⁺ Signaling (asdescribed below).

Ca²⁺ signaling studies were performed using a FLIPR TETRA system(Molecular Devices, Sunnyvale, Calif., USA) in the 384-format. This is ahigh-throughput instrument for cell-based assays to monitor Ca²⁺signaling associated with GPCRs and ion channels. Cells were seeded at adensity of 5×10⁴ cells/well in BioCoat poly-D-lysine coated, black wall,clear bottom 384-well plates (BD Biosciences, Franklin lakes, NJ, USA)and allowed to attach overnight in an incubator at 37° C. The cells werethen washed twice with HBSS-HEPES buffer (Hanks' balanced salt solutionwithout bicarbonate and phenol red, 20 mM HEPES, pH 7.4) using an ELx405Select CW Microplate Washer (BioTek, Winooski, Vt., USA). After 60 minof dye-loading in the dark using the Ca²⁺-sensitive dye Fluo-4AM(Invitrogen, Carlsbad, Calif., USA), at a final concentration of2×10⁻⁶M, the plates were washed 4 times with HBSS-HEPES buffer to removeexcess dye and leaving 50 μl of buffer in each well. The plates werethen placed in the FLIPR TETRA instrument and allowed to equilibrate at37° C. Compounds were added in a 25 μl volume to each well to give finalconcentrations of 0.1 μM, 0.3 μM, 1 μM, 3 μM, 10 μM, and 30 μM; or 0.067μM, 0.1 μM, 0.2 μM, 0.3 μM, 0.67 μM, and 1 μM for cells over-expressingTP receptors. After 4.5 minutes, a 7-point serial dilution of thestandard agonist for the corresponding receptor, in a 25 μl volume wasinjected at the final concentrations from 10⁻¹¹M to 10⁻⁵M in 10-foldserial dilution increments for cells expressing human recombinant DP₁,EP₁, EP₂, EP₃, EP₄, FP, and IP receptors. The dose range for thestandard agonist for human recombinant TP receptors was from 10⁻¹²M to10⁻⁶M. HBSS-HEPES buffer was used as the negative control for thestandard agonists. Cells were excited with LED (light emitting diode)excitation at 470-495 nm and emission was measured through an emissionfilter at 515-575 nm. Assay plates were read for 3.5 minutes using theFLIPR^(TETRA). The peak increase in fluorescence intensity was recordedfor each well. On each plate, negative controls, dose response ofpositive controls, and co-treatments of antagonist-agonist for each dosewere in triplicates. Standard agonists were as follows: DP=BW 245C,EP₁-EP₄=PGE₂, FP=17-phenyl-PGF_(2α), IP=Cicaprost, and TP=U-46619. Thepeak fluorescence change in each well containing drug was expressedrelative to vehicle controls with the standard agonist at 10⁻⁶M (thepositive control). To obtain concentration-response curves, compoundswere tested in triplicate in each plate over the desired concentrationrange.

Data Processing

All plates were subjected to appropriate baseline corrections. Maximumfluorescence values were exported. The raw data of n=1 was firstprocessed by Activity Base using nonlinear regression curve fit tocalculate the percentage activity of each data point relative to thepositive control (=10⁻⁶M of the standard agonist). Then n=3 of this datawere exported to GraphPad Prism 4 to calculate the average EC₅₀ of thestandard agonist, and the IC₅₀ (the concentration of the antagonistrequired to inhibit half the standard agonist activity) were calculatedusing nonlinear regression curve fit, with constraints of bottomconstant equal to 0 and top constant equal to 100. Calculation ofKb=[Antagonist Concentration]/(IC₅₀/EC₅₀-1). When no antagonism wasdetected or when Kb≧10,000 nM, the antagonist is defined as not active(NA).

The results of the above testing are reported in TABLE 1, below.

Exam- ple FP DP EP₁ EP₂ EP₃ EP₄ IP TP 1 560 2100 180 8700 5200 70 2200150 2 160 1300 140 2900 1100 20 1100 110 3 50 1200 16 3400 3000 60 12004 4 20 700 6 1800 1500 25 800 2 5 340 2100 130 NA NA 50 5200 40 6 24007100 NA NA NA NA NA 150 7 300 1900 45 4400 NA 1800 1300 20 8 200 2600220 5000 NA 1300 2800 2100 9 20 1200 90 3200 4900 3000 1350 PAgonist 1030 440 50 500 1100 20 400 20 11 120 900 120 2000 6500 110 5500 120 12120 1600 360 7900 NA 1150 5000 44 13 20 1200 50 1900 8500 2700 600 90014 30 600 20 400 1500 15 340 600 15 130 1800 190 3300 8400 200 1800 2016 3000 1500 90 NA 4000 600 6600 400 17 2300 3500 40 NA NA 600 NA 330018 20 1400 40 NA 4000 60 6500 4 19 16 1200 12 8800 3600 14 4600 50 20 13500 30 NA NA 30 2700 50 21 30 100 14 3500 2200 70 900 13 22 140 1700 16NA NA 350 6000 5 23 170 900 30 7100 1200 50 500 1 24 40 160 20 4500 2440150 1430 80 25 180 220 27 9300 4500 160 1030 50 26 500 1700 80 NA 330070 1800 18 27 200 1600 110 3640 2600 53 440 20 28 70 730 43 9200 2220 401530 7 29 30 140 1700 16 NA NA 350 6000 5 31 170 900 30 7100 1200 50 5201 32 50 1700 210 NA NA 5000 7400 50 33 70 350 70 2600 1400 30 400 1 343200 5400 70 NA NA NA NA 100 35 4300 1900 4200 NA NA 670 NA 1200 36 5801100 60 2900 4000 1200 200 3 37 NA 1300 480 NA 3400 700 NA 200 38 1100630 70 2100 1700 400 60 3 39 NA 1000 1200 NA 5500 1600 4900 110 40 2701000 60 900 12000 2500 PAg Ag 41 NA 4700 NA NA NA NA 9800 7400 42 900160 24 NA 1900 1800 3400 20 43 2200 2000 1200 NA 5500 1600 4900 110 441400 PAg 240 NA 1600 3200 PAg 1 45 1400 2800 23 NA NA 2000 7000 80 46 NA2500 7100 NA NA NA NA 150 47 4700 700 2000 NA NA NA 4800 NA 48 NA NA 260NA NA NA NA 500 49 70 3500 540 NA NA 50 3200 6 50 4900 2400 90 NA 71001800 NA 5700 51 110 600 70 NA 2600 270 1100 50 52 11 2300 24 3800 210010 NA 2 53 230 NA 1500 NA NA NA NA 1200 54 1100 9900 1300 NA NA 2700 NA640 55 40 1200 40 NA NA 2100 NA 300 56 24 1800 24 NA 8800 150 4100 5 57190 5500 27 NA NA 1300 NA 150 58 60 1800 30 NA 9800 380 NA 70 59 1300520 280 NA 5400 190 540 320 60 2500 580 410 7500 5100 150 630 410 611500 740 180 NA NA 760 1750 300 62 NA 5800 NA NA NA NA NA NA 63 2400 NA1200 NA 7400 2500 5000 180 64 190 260 5 3100 2900 50 700 8 65 PAg 150040 6500 4700 55 880 52 66 23 NA 50 NA NA 1400 4600 320 67 100 NA 60 NANA 340 NA 160 68 NA NA NA NA NA 9700 6600 NA 69 800 3700 250 NA 7900 1303000 550 70 NA 2200 200 NA NA 6000 NA 320 71 120 NA 100 NA NA 280 NA 60072 25 1500 10 NA NA 220 2000 3 73 430 NA 80 NA NA NA 9000 8 74 660 29060 NA 2800 440 1400 20 75 330 1300 20 6400 NA 280 4400 300 76 660 290 60NA 2800 440 1400 20 77 9600 3600 900 9200 NA 1500 NA 1100 78 800 3800145 NA NA 35 3000 16 79 80 2000 11 NA 8700 80 7000 8

As shown in TABLE 1, the preferred compounds of this invention are panantagonists having activity at the FP, DP₁, EP₁, EP₄ and TP receptors,but are inactive at the IP, EP₂ and EP₃ receptors. Thus, these compoundshave a biological selectivity profile making them useful in treatingdiseases and conditions which are ameliorated by the IP/EP₂ and/or EP₃receptor stimulation, without the symptoms side effects mediated by theFP, DP, EP₁, EP₄ and TP receptors. Also, based on the data generated forthis TABLE 1, it appears that the 5-carboxylic acid compounds are moreactive at the EP₁ and EP₄ receptors than the 4 or 6-carboxylic acidcompounds. Therefore, the 5-carboxylic acid compounds are preferred.

Thus, the compounds of this invention compound may be administered totreat DP1, FP, EP₁, TP and/or EP4 receptor mediated diseases orconditions.

For example, said condition or disease may be related to inflammation,or said, FP, EP₁, TP and/or EP₄ receptor mediated condition or diseasemay be selected from the group consisting of allergic conditions,asthma, allergic asthma, allergic rhinitis, uveitis and relateddisorders, atherosclerosis, blood coagulation disorders, bone disorders,cancer, cellular neoplastic transformations, chronic obstructivepulmonary diseases and other forms of lung inflammation, congestiveheart failure, diabetic retinopathy, diseases or conditions requiring atreatment of anti-coagulation, diseases requiring control of boneformation and resorption, endometriosis, fertility disorders, gangrene,glaucoma, hyperpyrexia, immune and autoimmune diseases, inflammatoryconditions, metastic tumor growth, migraine, mucus secretion disorders,nasal congestion, nasal inflammation, occlusive vascular diseases,ocular hypertension, ocular hypotension, osteoporosis, rheumatoidarthritis, pain, perennial rhinitis, pre-term labor, pulmonarycongestion, pulmonary hypotension, Raynaud's disease, rejection in organtransplant and by-pass surgery, respiratory conditions, hirsutism,rhinorrhea, shock, sleep disorders, and sleep-wake cycle disorders.

The compounds of the present invention may be administered as a surgicaladjunct in ophthalmology for cataract removal and artificial lensinsertion, ocular implant procedures, photorefractive radial keratotomyand other ophthalmogical laser procedures or as a surgical adjunct in aprocedure involving skin incisions, relief of pain and inflammation andscar formation/keloids post-surgery, for treating sports injuries andgeneral aches and pains in muscles and joints.

Preferably, said DP₁, FP, EP₁, TP, and/or EP₄ receptor mediatedcondition or disease is an EP₁ and/or EP₄ receptor mediated condition ordisease. Preferably, said DP₁, FP, EP₁, TP and/or EP₄ receptor mediatedcondition or disease is an allergic condition, e.g. an dermatologicalallergy, or an ocular allergy, or a respiratory allergy, e.g. nasalcongestion, rhinitis, and asthma.

The condition or disease may be related to pain. The condition ordisease may be selected from the group consisting of arthritis,migraine, and headache. The condition or disease may be associated withthe gastrointestinal tract, wherein said condition or disease may bepeptic ulcer, heartburn, reflux esophagitis, erosive esophagitis,non-ulcer dyspepsia, infection by Helicobacter pylori, alrynitis, andirritable bowel syndrome.

The condition or disease may be selected from the group consisting ofhyperalgesia and allodynia, or said condition or disease may be relatedto mucus secretion, wherein said mucus secretion is gastrointestinal, oroccurs in the nose, sinuses, throat, or lungs.

The condition or disease is related to abdominal cramping, e.g. saidcondition, menstrual cramping or disease may be irritable bowelsyndrome. The condition or disease may be a bleeding disorder, or asleep disorder, or mastocytosis.

The condition or disease may be associated with elevated bodytemperature, or ocular hypertension and glaucoma, or ocular hypotension.The condition may relate to surgical procedures to treat pain,inflammation and other unwanted sequelae wherein said surgical procedureincludes incision, laser surgery or implantation.

The present invention also relates to a method of treating inflammationresulting from inflammatory diseases characterized by monocyticinfiltration caused by the secretion of cytokines and/or chemokines byadministration, to a patient in need of said treatment, of apharmaceutical composition comprising a compound of the presentinvention

The current finding that the compounds of this invention are effectivein attenuating the production of TNF family cytokines (TNFα), and theclassical interleukin-1 (IL-1) family cytokines is especially important.These cytokines exert a broad spectrum of biological and pathologicaleffects. They play key roles in inflammation and RA pathogenesis bystimulating the release of multiple proinflammatory cytokines, includingthemselves, through the NFκB signaling pathway. Although alleviating thesymptoms of RA in 50-65% of patients, a TNFα antibody is very expensiveto use compared to chemically synthesized small molecules, inconvenientto administer usually requiring injections, and has been linked totuberculosis, lymphoma, and other adverse effects. Unlike a TNFαantibody that totally eliminates all circulating TNFα in the system; thecompounds of this invention only attenuate the production of TNFα byinhibiting proinflammatory PG receptors. Therefore, the adverse effectsassociated with a TNFα antibody in elevating infectious and canceroustendency is less likely.

Proinflammatory elements TNF, RANTES, and MCP-1 are involved in thecascade of events in the early and late stages of atherosclerosis.Plasma MCP-1 levels have been linked to cardiovascular disease riskfactors in clinical studies. Platelet activation leads to the release ofMIP-1α, RANTES, and IL-8, which attract leukocytes and further activateother platelets. These evidences provide a direct linkage betweenhomeostasis, infection, and inflammation and the development ofatherosclerosis. The compounds of this invention are able to targetmultiple biomarkers of inflammation, thrombosis, and atherothrombosissimultaneously, which may confer pharmaceutical potential on thecompounds of this invention in treating atherosclerosis andatherothrombosis. As a result, the compounds of this invention areunlikely to be associated with cardiovascular liability as in the caseof the COXIBs, conversely it may even have a beneficial effect oncardiovascular function.

In summary, because of their ability to suppress the synthesis of somekey proinflammatory cytokines/chemokines IL-8, MCP-1, MDC, RANTES, andTNFα, the compounds of the present invention are believed to be, notonly at least as effective as COXIBs and NSAIDs in RA treatment, butalso are a safer therapy in RA treatment. They are also a potentialtherapy for cardiovascular diseases.

The compounds of this invention are believed to treat or preventinflammation at least in part by the decreasing the amount of thesecretion of certain cytokines and/or chemokines that result from theexposure of the patient to a stimulant. In particular, the secretion ofVEGF, MIP-1β, IL-8, MCP-1, MDC, and RANTES may be reduced in thoseinstances where said secretions are triggered by lipopolysaccharides(LPS) and or TNFα.

Interleukin-8 (IL-8): functions as a potent chemoattractant andactivator of neutrophils, IL-8 is produced in response to stimulationwith either IL-1 or TNFα. IL-8 not only accounts for a significantproportion of the chemotactic activity for neutrophils in rheumatoidarthritis (RA) synovial fluids, but also is a potent angiogenic factorin the RA synovium. Monocyte chemoattractant protein-1 (MCP-1, orCCL-2): is not only believed to play a role in inflammatory diseasescharacterized by monocytic infiltration, such as rheumatoid arthritis(“RA”), psoriasis, and atherosclerosis, but is also implicated in otherdiseases, such as atopic dermatitis, renal disease, pleurisy, allergyand asthma, colitis, endometriosis, polymyositis and dermatomyositis,uveitis, restenosis, brain inflammation and obesity. MCP-1 also controlsleukocyte trafficking in vascular cells involved in diabetes anddiabetes-induced atherosclerosis. MCP-1 antibodies are potentialtherapeutic agents for treating MCP-1/CCR2-mediated multipleinflammatory diseases.

Tumor necrosis factor α (TNFα): mainly secreted by macrophages andrecognized for its importance in activating the cytokine cascade. TNFαstimulates the production of proinflammatory cytokines/chemokines,collagenases, metalloproteinases, and other inflammatory mediators;activates endothelial cells and neutrophils; promotes T- and B-cellgrowth, as well as stimulating bone resorption. The TNFα antibodyinfliximab not only decreases the production of local and systemicproinflammatory cytokines/chemokines, but also reduces serum MMP-3production, nitric oxide synthase activity, VEGF release, andangiogenesis in inflamed joints.

Macrophage-derived chemokine (MDC) induces chemotaxis formonocyte-derived dendritic cells, activated T cells and natural killer(NK) cells (Ho et al., 2003). Highly expressed by the three major celltypes involved in allergic inflammation: eosinophils, basophils, and Th2lymphocytes (Garcia et al., 2005), as well as highly expressed in atopicdermatitis (Pivarcsi et al., 2005), MDC plays a role in inflammatorydiseases such as allergic asthma and atopic dermatitis (Ho et al.,2003). Significantly enhanced in keratinocytes of patients with atopicdermatitis, MDC could be a candidate therapeutic target for inflammatoryskin disease such as atopic dermatitis (Qi et al., 2009). MDC is alsoimplicated in disease activity of RA. After combination treatment withthe disease-modifying anti-rheumatic drugs leflunomide and methotrexatein RA patients, plasma MCP-1 and MDC concentrations were significantlylower, and so was the recruitment of inflammatory cells into the sitesof inflammation (Ho et al., 2003). Moreover, MDC also amplify plateletactivation and has been associated with the pathogenesis ofatherosclerotic disease including thrombosis (Gleissner et al., 2008).

Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES)is a chemoattractant for blood monocytes, memory T-helper cells andeosinophils, and plays an active role in recruiting leukocytes intoinflammatory sites. It also stimulates the release of histamine frombasophils, activates eosinophils and causes hypodense eosinophils, whichare associated with diseases such as asthma and allergic rhinitis.RANTES receptor CCR5 is also expressed on cells involved inatherosclerosis (e.g. monocytes/macrophages, T lymphocytes, or Th1-typecells), and is specialized in mediating RANTES-triggered atheroscleroticplaque formation (Zernecke et al., 2008). Like MCP-1, stimulation withRANTES enhances production of IL-6 and IL-8 in RA fibroblast-likesynovial cells; elevated MMP-3 production by chondrocytes, and inhibitedproteoglycan synthesis and enhanced proteoglycan release from thechondrocytes (Iwamoto et al., 2008). Both MCP-1 and RANTES were found toplay an important role in allergic lung inflammation, lung leukocyteinfiltration, bronchial hyper-responsiveness, and the recruitment ofeosinophils in the pathogenesis of asthma (Conti et al., 2001). Similarto MCP-1, RANTES also enhances the inflammatory response within thenervous system, which plays an apparent role in the pathogenesis ofmultiple sclerosis (Conti et al., 2001) Inhibitors for RANTES mayprovide clinical benefits in treating inflammation, CNS disorders,parasitic disease, cancer, autoimmune and heart diseases (Castellani etal., 2007). Thus the compounds of the present invention, given locallyor systemically, may be useful for treatment or alleviating symptoms ofT cell mediated autoimmune disorders such as RA and multiple sclerosis.

While the use of the compounds of this invention are believed todecrease the secretion of the above cytokines, it is also believed thatthe compounds of this invention are effective to decrease the secretionof ENA-7, PAI-1, CD-10, G-CSF, GM-CSF, IL-1α and IL-18, as well.

The compounds of this invention may be also tested for efficacy intreating uveitis as described below.

Arachidonate Induced Uveitis

The rational for this protocol is to use arachidonate to directlyproduce ocular anterior segment uveitis, as opposed to usinglipopolysaccharide (LPS) to indirectly release arachidonic acid.

Induction of Uveitis:

Conscious male or female Dutch-belted pigmented rabbits weighing 2.5-3kg are used for all in vivo slit lamp studies. Four animals are employedper test group. The right eye of each animal receiving 35 μl oftopically administered test and the contralateral left eye of eachanimal receiving 35 μl of topically administered vehicle (t=0 minutes),followed 30 minutes later by treatment with 35 μl of 0.5% sodiumarachidonate onto the surface of both eyes (t=30 minutes). Both eyes areexamined by slit lamp 60 minutes following sodium arachdionate challenge(t=90 minutes) at 16× magnification under both white light and bluelight illumination at an approximate angle of 45° through 1 mm and 5 mmslit widths.

Measurement of Anterior Chamber Leukocyte Infiltration:

Anterior chamber leukocyte infiltration is measured using a numericalscoring system to estimate cell number per field defined by a 5 mm slitwidth: 0=no cells per field (no response); 1=1-10 cells per field(mild); 2=11-20 cells per field (moderate); 3=26-50 cells per field(severe); 4=>50 cells per filed (florid). Results are reported as themean score value±S.E.M.

The compounds of this invention may be tested according to the methoddescribed in “Characterization of Receptor Subtypes Involved inProstanoid-Induced Conjunctival Pruritis and Their Role in MediatingConjunctival Itching”, Vol. 279, No. 1, (JPET) 279, 137-142′ 1996 fortheir efficacy in alleviating itch to thereby indicate that thecompounds of this invention are useful in treating allergicconjunctivitis. This reference is hereby incorporated by reference.

While the use of the compounds of this invention are believed todecrease the secretion of the above cytokines, it also is believed thatthe compounds of this invention are effective to decrease the secretionof ENA-7, PAI-1, CD-10, G-CSF, GM-CSF, IL-1α and IL-18, as well.

Finally, said condition that may be treated with the compounds of thisinvention may be related to pain and inflammation and post-surgical scarand keloid formation.

In view of the various diseases and conditions that may be treated withthe compositions of this invention there is provided a pharmaceuticalproduct comprising a compound having the following formula:

Wherein: X is N or CR₇;

A is N or CR₇ with the proviso that at least one A is N and when each Ais N, R₂ is absent;Y is (CH₂)_(m), wherein m is 0 or an integer of from 1 to 3;Z is selected from the group consisting of O, S, SO, SO₂ and (CH₂)_(p),wherein p is 0 or an integer of from 1 to 3;W is hydrocarbyl or substituted hydrocarbyl;R₁ is selected from the group consisting of OR₇, NH₂, N(R₇)₂, andN(R₇)SO₂R₇;R₂ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;R₃ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;R₄ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;and/or a pharmaceutically acceptable salt or a prodrug thereof.The compounds of the present invention may be formulated, packaged andlabeled for the treatment or prevention of a disease or conditionselected from the group consisting of uveitis, allergic conditions,asthma, allergic asthma, allergic rhinitis, atherosclerosis, bloodcoagulation disorders, bone disorders, cancer, cellular neoplastictransformations, chronic obstructive pulmonary diseases and other formsof lung inflammation, congestive heart failure, diabetic retinopathy,diseases or conditions requiring a treatment of anti-coagulation,diseases requiring control of bone formation and resorption, fertilitydisorders, hyperpyrexia, endometriosis gangrene, glaucoma, hypothermia,immune and autoimmune diseases, inflammatory conditions, metastic tumorgrowth, migraine, mucus secretion disorders, nasal congestion, nasalinflammation, occlusive vascular diseases, ocular hypertension, ocularhypotension, osteoporosis, pain, perennial rhinitis, pre-term laborpulmonary congestion, pulmonary hypotension, Raynaud's disease,rejection in organ transplant and by-pass surgery, respiratoryconditions, rheumatoid arthritis, rhinorrhea, shock, sleep disorders,sleep-wake cycle disorders, sports injuries, muscle aches and pains, andsurgical adjunct for minimizing pain, inflammation and scar/keloidformation.

Those skilled in the art will readily understand that for administrationthe compounds disclosed herein can be admixed with pharmaceuticallyacceptable excipients which, per se, are well known in the art.Specifically, a drug to be administered systemically, it may beformulated as a powder, pill, tablet or the like, or as a solution,emulsion, suspension, aerosol, syrup or elixir suitable for oral orparenteral administration or inhalation.

For solid dosage forms, non-toxic solid carriers include, but are notlimited to, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, the polyalkylene glycols, talcum,cellulose, glucose, sucrose and magnesium carbonate. The solid dosageforms may be uncoated or they may be coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distcarate maybe employed. They may also be coated by the technique described in theU.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 which are herebyincorporated by reference to form osmotic therapeutic tablets forcontrol release. Liquid pharmaceutically administrable dosage forms can,for example, comprise a solution or suspension of one or more of thecompounds of the present invention and optional pharmaceutical adjutantsin a carrier, such as for example, water, saline, aqueous dextrose,glycerol, ethanol and the like, to thereby form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of nontoxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like. Typical examples of such auxiliary agents are sodiumacetate, sorbitan monolaurate, triethanolamine, sodium acetate,triethanolamine oleate, etc. Actual methods of preparing such dosageforms are known, or will be apparent, to those skilled in this art; forexample, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 16th Edition, 1980. The composition of theformulation to be administered, in any event, contains a quantity of oneor more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectableformulations can be prepared in conventional forms, either as liquidsolutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol, ethanoland the like. In addition, if desired, the injectable pharmaceuticalcompositions to be administered may also contain minor amounts ofnon-toxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like.

The amount of the presently useful compound or compounds of the presentinvention administered is, of course, dependent on the therapeuticeffect or effects desired, on the specific mammal being treated, on theseverity and nature of the mammal's condition, on the manner ofadministration, on the potency and pharmacodynamics of the particularcompound or compounds employed, and on the judgment of the prescribingphysician. The therapeutically effective dosage of the presently usefulcompound or compounds is preferably in the range of about 0.5 ng/kg/dayor about 1 ng/kg/day to about 100 mg/kg/day.

For ophthalmic application, solutions are often prepared using aphysiological saline solution as a major vehicle. Ophthalmic solutionsshould preferably be maintained at a comfortable pH with an appropriatebuffer system. The formulations may also contain conventional,pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

Similarly, an ophthalmically acceptable antioxidant for use in thepresent invention includes, but is not limited to, sodium metabisulfite,sodium thiosulfate, acetylcysteine, butylated hydroxyanisole andbutylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edentatedisodium, although other chelating agents may also be used in place orin conjunction with it.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound of the present invention are employed.Topical formulations may generally be comprised of a pharmaceuticalcarrier, cosolvent, emulsifier, penetration enhancer, preservativesystem, and emollient.

The actual dose of the compounds of the present invention depends on thespecific compound, and on the condition to be treated; the selection ofthe appropriate dose is well within the knowledge of the skilledartisan.

The present invention is not to be limited in scope by the exemplifiedembodiments, which are only intended as illustrations of specificaspects of the invention. Various modifications of the invention, inaddition to those disclosed herein, will be apparent to those skilled inthe art by a careful reading of the specification, including the claims,as originally filed. It is intended that all such modifications willfall within the scope of the appended claims.

What is claimed is:
 1. A compound represented by the following formula:

wherein X is N or CR₇; A is N or CR₇ with the proviso that at least oneA is N and when each A is N, R₂ is absent Y is (CH₂)_(m) wherein m is 0or an integer of from 1 to 3; Z is selected from the group consisting ofO, S, SO, SO₂ and (CH₂)_(p), wherein p is 0 or an integer of from 1 to3; W is hydrocarbyl or substituted hydrocarbyl; R₁ is selected from thegroup consisting of OR₇, NH₂, N(R₇)₂, and N(R₇)SO₂R₇; R₂ is selectedfrom the group consisting of H, hydroxyl, alkyl, aryl, alkoxy, aryloxy,halogen, nitro, amino, cyano and hydroxyl halogen, nitro, amino andcyano-substituted alkyl, aryl, alkoxy or aryloxy; R₃ is selected fromthe group consisting of H, hydroxyl, alkyl, aryl, alkoxy, aryloxy,halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino andcyano-substituted alkyl, aryl, alkoxy or aryloxy; R₄ is selected fromthe group consisting of H, hydroxyl, alkyl, aryl, alkoxy, aryloxy,halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino andcyano-substituted alkyl, aryl, alkoxy or aryloxy; and R₇ is selectedfrom the group consisting of H, hydrocarbyl and substituted hydrocarbyl.2. The compound of claim 1 wherein R₇ is selected from the groupconsisting of carbocyclic aryl and alkyl.
 3. The compound of claim 1wherein said compound is represented by the formula II:


4. The compound of claim 3 wherein R₁ is OH.
 5. The compound of claim 3wherein R₂ is selected from the group consisting of H, alkyl and halogensubstituted alkyl
 6. The compound of claim 5 wherein R₂ is selected fromthe group consisting of fluoro-substituted alkyl.
 7. The compound ofclaim 6 wherein X is N or CH.
 8. The compound of claim 1 wherein saidcompound is represented by formula III


9. The compound of claim 8 wherein R₃ is selected from the groupconsisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro,amino, cyano and hydroxy, halogen, nitro, amino and cyano-substitutedalkyl, aryl, alkoxy or aryloxy.
 10. The compound of claim 8 wherein R₃is chloro or bromo.
 11. The compound of claim 8 wherein R₄ is selectedfrom the group consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy,halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino andcyano-substituted alkyl, aryl, alkoxy or aryloxy.
 12. The compound ofclaim 8 wherein W is selected from the group consisting of alkyl, aryl,alkoxy, aryloxy and hydroxy, halogen, nitro, amino and cyano-substitutedalkyl, aryl, alkoxy or aryloxy.
 13. The compound of claim 8 wherein W isselected from the group consisting of alkyl, aryl, alkoxy, aryloxy andhydroxy, halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxyor aryloxy.
 14. The compound of claim 8 wherein W is alkyl.
 15. Thecompound of claim 8 wherein W is a branched chain alkyl.
 16. Thecompound of claim 8 wherein the compounds are PG antagonists.
 17. Thecompounds of claim 8 wherein the compounds are useful for treating orreducing the symptoms of a DP₁, FP, EP₁, TP EP1 or EP₄ receptor mediatedcondition or disease.
 18. A compound selected from the group consistingof: 1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indole-5-carboxylic acid;1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic acid;1-(2-Chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;1-(2-Bromo-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;1-[2-Bromo-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic acid;1-[2-Chloro-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylic acid;1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid;1-(2-Benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic acid;1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylicacid; 1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylicacid; 1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylicacid; 1-(2-Benzyloxy-5-bromo-benzyl)-1H-indazole-5-carboxylic acid;1-[5-Bromo-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic acid;1-(5-Bromo-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic acid;1-(5-Bromo-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic acid;2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid;2-(5-Bromo-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid;1-(2-(Trifluoromethyl)-5-isobutoxy-benzyl)-1H-indazole-5-carboxylicacid;1-(5-Bromo-2-cyclopropyl-2-methylmethoxy-benzyl)-1H-indazole-5-carboxylicacid; 1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylicacid; 1-(5-Bromo-2-isobutoxy-benzyl)-3-methyl-1H-indazole-5-carboxylicacid;1-(2-isobutoxy-5-trifluoromethoxy-benzyl)-3-methyl-1h-indazole-5-carboxylicacid;1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-3-methyl-1h-indazole-5-carboxylicacid; 1-(5-chloro-2-isobutoxy-benzyl)-3-methyl-1h-indazole-5-carboxylicacid;1-(2-isobutoxy-5-trifluoromethyl-benzyl)-3-methyl-1h-indazole-5-carboxylicacid;1-[2-(2-ethyl-butoxy)-5-trifluoromethyl-benzyl]-3-methyl-1h-indazole-5-carboxylicacid;1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-3-methyl-1h-indazole-5-carboxylicacid;1-[5-bromo-2-(1-methyl-cyclopropylmethoxy)-benzyl]-3-methyl-1h-indazole-5-carboxylicacid;1-[5-chloro-2-(1-methyl-cyclopropylmethoxy)-benzyl]-3-methyl-1h-indazole-5-carboxylicacid;1-(5-Bromo-2-isobutoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid;1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid;1-[2-(4-Chloro-benzyloxy)-5-trifluoromethyl-benzyl]-1H-indazole-5-carboxylicacid;1-(2-Cyclopentylmethoxy-5-trifluoromethyl-benzyl)-1H-indazole-5-carboxylicacid; 1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-4-carboxylicacid; 2-(5-Chloro-2-cyclopropylmethoxy-benzyl)-2H-indazole-4-carboxylicacid; 1-(5-Chloro-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid;2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-4-carboxylic acid;1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-4-carboxylic acid;2-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-2H-indazole-4-carboxylic acid;1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-4-carboxylicacid;2-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-2H-indazole-4-carboxylicacid; 1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-6-carboxylic acid;2-(5-Bromo-2-isobutoxy-benzyl)-2H-indazole-6-carboxylic acid;1-(5-Bromo-2-cyclopentylmethoxy-benzyl)-1H-indazole-6-carboxylic acid;2-(5-Bromo-2-cyclopentylmethoxy-benzyl)-2H-indazole-6-carboxylic acid;1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylic acid;1-(5-Chloro-3-fluoro-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;1-(2-Isobutoxy-5-methanesulfonyl-benzyl)-1H-indazole-5-carboxylic acid;1-(4,5-Dichloro-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;1-(3-Isobutoxy-6-methyl-pyridin-2-ylmethyl)-1H-indazole-5-carboxylicacid; 1-[5-Bromo-2-(1-ethyl-propoxy)-benzyl]-1H-indazole-5-carboxylicacid;1-[5-Bromo-2-(2,2-dimethyl-propoxy)-benzyl]-1H-indazole-5-carboxylicacid;1-[5-Bromo-2-(2-hydroxy-2-methyl-propoxy)-benzyl]-1H-indazole-5-carboxylicacid; 1-(5-Hydroxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;1-[5-(2,2-Difluoro-ethoxy)-2-isobutoxy-benzyl]-1H-indazole-5-carboxylicacid; 1-(5-Difluoromethoxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylicacid;1-(5-Chloro-2-isobutoxy-benzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid;1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid;1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid;1-[5-CHLORO-2-(2-ethyl-butoxy)-benzyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid;1-(5-Chloro-2-isobutoxy-benzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid;1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazolo[3,4-c]pyridine-5-carboxylicacid amide;1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazolo[3,4-c]pyridine-5-carboxylicacid; 1-(5-bromo-2-isobutoxy-benzyl)-3-ethyl-1h-indazole-5-carboxylicacid;1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-3-ethyl-1h-indazole-5-carboxylicacid; 1-(5-bromo-2-isobutoxy-benzyl)-2-methyl-1h-indole-5-carboxylicacid; 1-(5-bromo-2-isobutoxy-benzyl)-1h-indole-5-carboxylic acid;1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-2-methyl-1h-indole-5-carboxylicacid; 1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-indole-5-carboxylic acid;1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-indole-6-carboxylic acid;1-(2-isobutoxy-5-trifluoromethoxy-benzyl)-1h-indole-5-carboxylic acid;1-(5-bromo-2-isobutoxy-benzyl)-1h-pyrrolo[2,3-b]pyridine-5-carboxylicacid;1-(5-bromo-2-isobutoxy-benzyl)-1h-pyrrolo[3,2-b]pyridine-5-carboxylicacid;1-(2-isobutoxy-5-trifluoromethoxy-benzyl)-1h-pyrrolo[2,3-b]pyridine-5-carboxylicacid;1-(2-isobutoxy-5-trifluoromethoxy-benzyl)-3-methyl-1h-indole-5-carboxylicacid;1-[2-(2-ethyl-butoxy)-5-trifluoromethoxy-benzyl]-1h-pyrrolo[2,3-b]pyridine-5-carboxylicacid;1-[2-(2-ethyl-butoxy)-5-trifluoromethoxy-benzyl]-3-methyl-1h-indole-5-carboxylicacid;1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-benzoimidazole-5-carboxylicacid; 1-(5-bromo-2-isobutoxy-benzyl)-1h-benzoimidazole-5-carboxylicacid; 1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylicacid; 1-(2-Chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;1-(2-Bromo-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;1-[2-Bromo-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic acid;1-[2-Chloro-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylic acid;1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid;1-(2-Benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic acid;1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylicacid; 1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylicacid; 1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylicacid; 1-(2-Benzyloxy-5-bromo-benzyl)-1H-indazole-5-carboxylic acid;1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylicacid; 1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylicacid; 1-(5-Bromo-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylicacid; 2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid;2-(5-Bromo-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid;1-(2-(Trifluoromethyl)-5-isobutoxy-benzyl)-1H-indazole-5-carboxylicacid;1-(5-Bromo-2-cyclopropyl-2-methylmethoxy-benzyl)-1H-indazole-5-carboxylicacid; 1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylicacid; 1-(5-Bromo-2-isobutoxy-benzyl)-3-methyl-1H-indazole-5-carboxylicacid;1-(5-Bromo-2-isobutoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid; and,1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid.
 19. The compounds of claim 18 wherein the compounds are useful fortreating or reducing the symptoms of a DP₁, FP, EP₁, TP EP1 or EP₄receptor mediated condition or disease.
 20. The compound of claim 15which is useful for treating a disease or disorder selected from thegroup consisting of allergic conditions, asthma, allergic asthma,allergic rhinitis, uveitis and related disorders, atherosclerosis, bloodcoagulation disorders, bone disorders, cancer, cellular neoplastictransformations, chronic obstructive pulmonary diseases and other formsof lung inflammation, congestive heart failure, diabetic retinopathy,diseases or conditions requiring a treatment of anti-coagulation,diseases requiring control of bone formation and resorption,endometriosis, fertility disorders, gangrene, glaucoma, hyperpyrexia,immune and autoimmune diseases, inflammatory conditions, metastic tumorgrowth, migraine, mucus secretion disorders, nasal congestion, nasalinflammation, occlusive vascular diseases, ocular hypertension, ocularhypotension, osteoporosis, pre-term labor rheumatoid arthritis, pain,perennial rhinitis, pulmonary congestion, pulmonary hypotension,Raynaud's disease, rejection in organ transplant and by-pass surgery,respiratory conditions, hirsutism, rhinorrhea, shock, sleep disorders,and sleep-wake cycle disorders.